Med 21255

Fragment Informatics and Computational Fragment-Based Drug Design: An Overview and Update
Chunquan Sheng and Wannian Zhang

Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, Peoples Republic of China Published online 19 March 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.21255
Abstract: Fragment-based drug design (FBDD) is a promising approach for the discovery and optimization of lead compounds. Despite its successes, FBDD also faces some internal limitations and challenges. FBDD requires a high quality of target protein and good solubility of fragments. Biophysical techniques for fragment screening necessitate expensive detection equipment and the strategies for evolving fragment hits to leads remain to be improved. Regardless, FBDD is necessary for investigating larger chemical space and can be applied to challenging biological targets. In this scenario, cheminformatics and computational chemistry can be used as alternative approaches that can signicantly improve the efciency and success rate of lead discovery and optimization. Cheminformatics and computational tools assist FBDD in a very exible manner. Computational FBDD can be used independently or in parallel with experimental FBDD for efciently generating and optimizing leads. Computational FBDD can also be integrated into each step of experimental FBDD and help to play a synergistic role by maximizing its performance. This review will provide critical analysis of the complementarity between computational and experimental FBDD and highlight recent advances in new algorithms and successful examples of their applications. In particular, fragment-based cheminformatics tools, high-throughput fragment docking, and fragment-based de novo drug design will provide the focus of this review. We will also discuss the advantages and limitations of C 2012 different methods and the trends in new developments that should inspire future research.
Wiley Periodicals, Inc. Med. Res. Rev., 33, No. 3, 554598, 2013
Key words: computational fragment-based drug design; fragment informatics; fragment docking; fragment-based de novo design
Correspondence to: Wannian Zhang or Chunquan Sheng, Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, Peoples Republic of China. E-mail: zhangwnk@hotmail.com or shengcq@hotmail.com Medicinal Research Reviews, 33, No. 3, 554598, 2013 C 2012 Wiley Periodicals, Inc.
FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD 1. INTRODUCTION
r 555
The identication of small molecules that selectively bind to a biological target is the key step in drug discovery. High-throughput screening (HTS) is a routine method for hit or lead discovery in the pharmaceutical industry.1 It has proven to be effective in many research programs, particularly with improved lead-like libraries. Although HTS has produced a number of lead molecules for various drug targets, it also has several limitations. A HTS campaign usually screens 106 107 compounds, which only cover a small portion of drug-like chemical space (about 106 molecules2 ). Moreover, the hit rate of HTS is generally low and the resulting leads are difcult to be optimized into drug-like candidates, because many of them have large molecular weights (MWs) and are strongly hydrophobic.3 In this context, fragment-based drug design (FBDD) is becoming an alternative approach for drug discovery.4 Taking advantages of both random screening and structure-based drug design (SBDD), FBDD constructs novel lead structures from small molecular fragments. Since the introduction of the SAR by NMR method in 1996,5 FBDD has become a practical and promising tool in drug discovery.6 The workow of a FBDD study is depicted in Figure 1. The rst
Figure 1.
The complementarity between computational and experimental FBDD.
Medicinal Research Reviews DOI 10.1002/med
556
r SHENG AND ZHANG
part of FBDD is to identify weak to moderate binders of the desired target by fragment screening. The libraries for fragment screening contain hundreds to thousands of small and low MW fragments, which are screened at high concentration.7 Because the binding afnities of fragments are relatively weak (5 mM1 M), highly sensitive detection methods have been developed for this purpose.8 The biophysical techniques for fragment screening mainly include nuclear magnetic resonance (NMR),9 mass spectroscopy (MS),10, 11 X-ray crystallography,12 and surface plasmon resonance (SPR) spectroscopy.13, 14 Then, various optimization strategies can be used to increase the afnity and drug likeness of fragment hits to evolve them into highquality leads. The hit-to-lead optimization process may involve a combination of fragment linking, fragment evolution, fragment optimization, and fragment self-assembly, which is often guided by the structural information of the target-fragment complex.15 The lead optimization stage is technically similar to that of conventional SBDD. More than ten clinical candidates have been generated by the FBDD strategy.4 In 2011, the B-Raf inhibitor vemurafenib (Zelboraf),16 the rst FBDD derived drug, was approved by the FDA for the treatment of melanoma. It took only 6 years from concept to approval for vemurafenib. Inspired by these encouraging results, FBDD is attracting more and more attention from both the pharmaceutical industry and the academic community.1719 Compared to HTS, FBDD has several advantages, including generation of higher chemical diversity (sampling a larger chemical space), higher hit rates, and higher ligand efciency (LE = log IC50 / number of heavy atoms).20 However, current FBDD approaches also face some internal limitations and challenges. First, FBDD methods still cover a small fraction of the total diversity space. It is estimated that a library of 103 fragments can typically sample the chemical diversity space of 109 molecules. Although the combinatorial advantage of FBDD provides a signicant increase in diversity space relative to HTS, exploring a larger region of drug-like space is still needed. Second, current fragment screening methods demand signicant amounts, purity, solubility, and suitability of target proteins for labeling or crystallization. Although progress has been made, the successful application of FBDD to membrane proteins (e.g. G-protein coupled receptors, GPCR) remains a signicant challenge.21 Moreover, FBDD is more suitable for certain classes of targets whose binding site often consists of multiple distinctive subsites (such as kinases) as individual fragments may occupy different subsites and they can be joined later into complete molecules. On the other hand, the process of fragment optimization is often guided by structure-based design, which is difcult to be applied to targets whose structures are unknown. Third, most of the FBDD methods do not take ligand specicity or selectivity into account. Although there are good examples of selective fragments targeted to kinases, the methodologies of FBDD need to be improved to efciently identify fragments that bind to the sites responsible for target specicity.22 Fourth, the geometries and key interactions of the original fragment hits may be changed when they are evolved into lead compounds.23 New methods should be developed to efciently select proper linkers to bridge fragments, nd proper groups (fragments) to be added to the initial fragment hits, and predict the binding mode of the newly generated molecules. Last, the techniques of FBDD often require specialized equipment and specic expertise,24 which limits the broad application of FBDD. Cheminformatics and computational approaches provide an alternative to the experimental FBDD methods. The incorporation of computational methods into the FBDD process can signicantly improve the efciency and success rate of lead discovery and optimization. Moreover, the low-throughput nature of experimental FBDD makes computational tools an attractive way to explore larger commercially available fragment databases. Computational chemistry tools can signicantly improve the efciency of each step of FBDD, such as fragment library design, active site characterization, fragment hit discovery, and hit-to-lead-to-candidate optimization. Several reviews have covered the topic of computational FBDD approaches.2532 Our goal here
FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD
r 557
is to highlight recent advances of new algorithms, analyze their advantages and limitations, and discuss the trends to inspire future research. We will rst provide a comprehensive overview of the complementarity between computational and experimental FBDD. Then, a broad set of cheminformatics and computational FBDD tools as well as their successful applications will be discussed in detail. In particular, we will focus on recent advances of fragment-based cheminformatics tools, high-throughput fragment docking, and fragment-based de novo drug design.
2. OVERVIEW OF THE COMPLEMENTARITY BETWEEN COMPUTATIONAL AND EXPERIMENTAL FBDD Computational chemistry provides complementary methods for experimental FBDD, and has assisted the implementation of FBDD in an efcient and cost-effective manner. Computational approaches play an important role throughout the process of FBDD (Fig. 1). The construction of high-quality fragment libraries is the rst step in the FBDD process. The library for fragment screening should have good diversity to represent drug-like chemical space and also meet certain criteria of physicochemical properties, solubility and synthetic accessibility.7, 8, 33 Such properties can be quickly obtained by computational methods and then used as lters for commercially available fragment databases. Computational methods are also helpful to remove fragments with unwanted chemical groups and incorporate the most frequently occurring fragments from known drugs. The fragments also need to be highly soluble, because they are screened at a high concentration. Approaches for the prediction of aqueous solubility mainly include quantitative structureactivity relationships (QSAR) and quantitative structure property relationships (QSPR) modeling.34, 35 During the fragment screening stage, molecular docking has been used as a prescreen tool to reduce experimental efforts. Virtual fragment screening can also directly yield potent hits without using a direct detection technique of experimental FBDD. For the hits identied from fragment screening, computational approaches (e.g. substructure search and similarity-based search) can be used to facilitate hit expansion and obtain SAR information for a secondary screen. For example, a research group from Vertex used the NMR SHAPES36 method to identify several micromolar hits by performing a secondary screen on 500 compounds that were obtained from substructure and similarity searching around the fragment hits.37 Although hit expansion of existing compounds may be a practical approach, it is more desirable to design and synthesize totally new compounds using fragment hits as seeds. Computational analysis of a protein-hit complex can provide useful information to prioritize the most promising fragment hits for the subsequent fragment-to-lead process. Structure-based in silico methods can iteratively assist the buildup of the fragment hits into a new lead compound that possesses improved potency and drug likeness. For example, the selection of an appropriate linker to join fragment hits is of great importance to generate high-afnity ligands. The exibility of the linker is important for the binding geometries of the original fragment hits and the binding afnity of the resulting molecules.38 In this context, computational methods (e.g. de novo drug design algorithms39 ) are helpful to virtually screen linker libraries. Moreover, de novo drug design methods can not only signicantly aid the assembly of fragment hits into novel compounds, but can also automatically design novel ligands. Molecular docking and molecular dynamics simulations can efciently predict the binding afnity and binding pose of the designed ligands, and thus they are powerful tools for the evolution of fragments into potent leads.40, 41 According to Vangrevelings review,30 31 out of 36 successful FBDD examples used structure-based design tools for fragment-to-lead optimization. Such structure-based approaches are also popular for the optimization of the lead into a clinical candidate.29
558
r SHENG AND ZHANG
3. FRAGMENT INFORMATICS What is a fragment? It is difcult to give a precise denition. Generally, fragments are small, low MW and highly soluble molecules that have weak binding afnity with the target protein. Fragments are often used to build a larger lead compound with improved biological activity. Also, the term fragment can be regarded as a substructure or structural part of a more complex molecule. In 2003, Congreve et al. found that fragment hits possessed physicochemical properties that meet the criteria of the rule of three (RO3), namely (i) MW 300 Da; (ii) hydrogen bond donors and acceptors 3; (iii) LogP 3.42 Additional physicochemical properties for a 2 . Typically, fragment include three or less rotatable bonds and a polar surface area less than 60 A the MW of fragment hits is in the range of 120250 and the binding afnity is 30 M1 mM.15 More recently, modications or extensions of these rules have been suggested.4345 Molecular fragments have long been used as descriptors for chemical similarity searches or diversity analysis and played an important role for chemoinformatics analysis. In addition, fragments have also been associated with specic biological activities, privileged structural motifs of specic target families, and absorption, distribution, metabolism, excretion, and toxicity (ADME/T) proles.4648 In the following sections, recent progress of fragment informatics and its impact on FBDD will be described (Fig. 2). A. Fragmentation Approaches and Fragment Space Breaking molecules into fragments is the rst step in fragment mining or fragment informatics analysis. Fragmentation of molecules allows the comparison of molecules using standard
Figure 2.
The inuence of fragment informatics to FBDD.
r 559
cheminformatics approaches. Nowadays, there are various publicly or commercially available databases, such as PubChem,49 eMolecules,50 WOMBAT,51 ZINC,52 WDI,53 Medchem,54 MDDR,55 and CMC,56 that consist of structure, property, and/or biological activity data for millions of small molecules. These easily accessible databases provide useful sources for cheminformatics analysis. Fragments are often obtained by in silico fragmentation of molecular structures. The average size of fragments and the composition of the fragment population are determined by two important parameters: the maximum number of permitted bond deletions per iteration and the total number of iterations. A number of well-dened computational fragmentation schemes have been reported. They can be mainly classied into substructure methods and building block methods. The substructure approaches treat the fragment as a substructure of the molecules and aim to complete the analysis of all possible fragments.57 Such methods are not specic to fragments and are often used in QSAR or similarity searches. The building block methods mainly focus on chemically meaningful fragments and have wide applications in computational FBDD. Predened breaking rules are used to dissect molecules into building blocks. For example, building blocks can be dened as rings, functional groups, side chains, or linkers. Our group has decomposed the MDDR database55 into rings, linkers, and side chains, which can be used to build drug-like fragment libraries.58 Another efcient way of fragmentation is virtual retrosynthesis. RECAP is the most widely used method and employs some common chemical reactions as the rules to break structures.59 During the process of RECAP fragmentation, the bonds formed by one of these reactions are cleaved. RECAP has been successfully applied to explore the fragment space, analyze drug-like fragments in marketed drugs,60, 61 and construct synthetically feasible fragment libraries for de novo ligand design.62 More recently, Schulz et al. evaluated six different cheminformatics tools for the construction of a fragment library.63 An iterative removal protocol was proven to be the best method to design a diverse fragment library that can maximally represent the commercially available chemical space. Chemical fragment space means combinations of molecular fragments and their connection rules. A rather small number of fragments can span a huge space of virtual compounds due to the combinatorial explosion.64 Because the chemical space of fragments is signicantly smaller than that of drug-like molecules,65 good sampling in the fragment space may be achieved by FBDD. An important goal of fragment informatics analysis is to construct drug-like and chemically tractable fragment space that can generate potent active compounds against a large variety of targets.66 Mauser et al. generated thousand-size fragment space through fragmentation of the WDI 200453 and the Medchem0354 databases using the RECAP principle.67 The fragment space contained two subsets: a subset containing the most frequently occurring fragments (2039 fragments) and a substructure-based diverse subset (1923 fragments). Validation studies revealed that the two subsets were complementary to each other and that their combination covered a larger part of drug-like chemical space. Tanaka et al. performed network analysis of fragment libraries by extracting relatively small compounds from the ZINC database.52 Moreover, an efcient compound-prioritization method was proposed for fragment linking. The variety of linkers was also shown to be relatively important for molecular diversity when fragment linking was performed. More recently, the fragment subset of a large compound database was analyzed. Deursen et al. visualized 4.5 million fragments in PubChem and provided important information on the distribution of structural diversity.68 Although RECAP has been widely used, it only covers a very limited number of generally applicable reactions. Other methods constructed fragment spaces that avoid splitting known molecules by retrosynthetic rules. For example, Cramers group from Tripos developed the ChemSpace technology69 and AllChem70 to navigate through known chemistry by the Topomer search methodologies.71 Another study used the Feature Trees Fragment Space Search
560
r SHENG AND ZHANG
(Ftrees-FS) method64, 72 to generate a huge fragment space encoding about 5 1011 compounds based on established in-house synthetic protocols for combinatorial libraries.73
B. Fragment Frequency Analysis and Fragment Mining In terms of fragments, a great deal of information can be obtained from existing or virtual compound databases, such as the distribution of fragments types, their frequency of occurrence and co-occurrence. Fragment frequency analysis is typically useful for understanding the nature of fragmentactivity and fragmentdrug-likeness relationships. Cheminformatics analysis of the differences of fragments between drugs and nondrugs, or between various classes of drugs will provide medicinal chemists with useful information for prioritizing screening libraries or designing drug-like compounds. There are two types of fragment frequency analysis: occurrence analysis and co-occurrence analysis. Occurrence analysis means the characterization of fragment distributions in large databases, while co-occurrence analysis is used to compare fragment sets in a pairwise manner. Pioneering work on the analysis of drug-like fragments was performed by Bemis and Murcko.60, 61 They identied frequently occurred molecular frameworks and side chains in drug sets selected from the CMC database. A similar strategy has also been applied to various databases to nd drug-like fragments.7477 More recently, Wang and Hou provided an update on drug-like fragments analysis and identied high-quality fragments for drug design.78 Frequencies for three kinds of building blocks (ring system, drug scaffold, and small fragment) were calculated for a FDA-approved drug database (ADDS) and an extended drug dataset (EDDS). Most top fragments were found to be essentially common for both drug datasets. Moreover, there is signicant difference in the distribution of chemical fragments between oral drugs and injectable drugs.79 Therefore, compounds designed by marketed oral drug fragments are more likely to have good bioavailability. Fragments that are recurrent in compounds with different activities are relevant as a useful source for the design of multitarget ligands.80, 81 Sheridan et al. used common substructures from the MDDR database to identify fragment replacements in drug-like molecules82 and fragments that are associated with multiple biological activities.81 Drug-like bioisosteric groups have been identied by the cheminformatics analysis of the frequency of occurrence of organic substituents in more than 3 million molecules.83 Haubertin and Bruneau systematically analyzed one-to-one chemical replacements occurring in an in-house drug-like dataset of AstraZeneca and built a web-based database of historically observed chemical replacements.84 Furthermore, fragment frequency analysis has also been used to build predictive models for ADME/T prediction.85, 86 Bajoraths group introduced a new method named MolBlaster that used randomly generated fragment populations to evaluate molecular similarity relationships.87 MolBlaster generates fragment proles of molecules by random deletion of bonds in connectivity tables and quantitative comparisons using entropy-based metrics. The term fragment prole differs from molecular ngerprint, because it is randomly generated and does not depend on predened structural or property descriptors. Fragment prole can encode sufcient information for similarity evaluation, which has been developed into a new tool for ligand-based virtual screening.88 Furthermore, the same group developed a new methodology to mine and organize randomly generated molecular fragment populations.89 Unique fragment signatures were identied for molecular sets with similar activities, and then fragment pathways of biologically active molecules were mapped. The results indicated that compound class-specic information and activity-specic fragment hierarchies could be obtained from random fragment proles. More recently, Lounkine et al. developed a new approach termed FragFCA to identify molecular fragments and fragment combinations that are specic for compounds having different activity
r 561
proles or that are unique to highly potent molecules.90 FragFCA uses chemically intuitive queries of varying complexity to systematically identify sets of signature fragments in a exible and interactive manner, and is applicable to fragments derived by any fragmentation scheme. Lameijer et al. reported fragment mining results for the NCI database.91 The database was split into more than 60,000 fragments of varying types: ring systems, linkers (26 linkers) and substituents. After analyzing the fragment occurrence and co-occurrence, the authors identied chemical clich es that indicated the most-occurring fragments and frequently co-occurring pairs of fragments. The resulting fragment libraries and correlations can give medicinal chemists more ideas about lead optimization, clusters of biologically active structures, and relatively unexplored parts of chemical space. Analysis of fragment frequencies in biologically active compounds can also be used to build interpretable models for the prediction of activity and target space. A research group from Lilly described a simple approach for fragmentation of a literature-based dataset and constructed naive Bayes models for predicting potency in individual kinases by comparing the similarity of fragment ngerprints.76 The statistical models had good predictive ability for kinase potency in both retrospective and prospective tests. Moreover, the comparison of fragment distributions in active molecules is also useful to assess target similarity. This method based on fragment-derived similarities complements sequence-based comparisons and whole-molecule approaches.
C. Fragment Tree During the process of lead optimization in drug discovery, medicinal chemists often synthesize a series of analogues with a common or similar core fragment (scaffold). Thus, the structure of a biologically active compound can be dissected into scaffold and substituents (R-groups). In order to nd a highly potent compound against a given target, most medicinal chemistry efforts are focused on the variation of the composition of the scaffolds and the substituents. For a small dataset, the importance of the scaffolds and substituents are straightforward and the SARs can be easily understood. But for large databases, especially the one containing a series of similar scaffold substructures, it is difcult to clearly elucidate SAR. In this case, organizing the structures in the form of a hierarchical tree is often benecial to rationalize SAR. In a hierarchical tree, structures with a common core fragment are arranged in branches and each node is a substructure (fragment) shared by all of its descendent (smaller) nodes. A well-constructed hierarchical tree can bring insights into which core fragments and which peripheral substituents are responsible for the activity, toxicity, or other relevant properties. The methods for building a hierarchical tree are largely dependent on the nature of the dataset. If the compounds were synthesized by linking various substituents with similar core fragments in a stepwise manner, it is easy to construct a fragmentation tree on the basis of the synthetic procedures. A descendent hierarchy can also be constructed by using the known common scaffolds as the root fragments. However, scaffolds are not always known ahead of time for a collection of structurally similar molecules without specic information about common substructures. Thus, algorithms should be developed to determine which parts of a structure are most scaffold-like. Several methods have been developed for the extraction, identication, and classication of chemical scaffolds.9294 Using these approaches, the scaffold tree can be built and the scaffold universe of the dataset can be visualized. More recently, Clark et al. reported new algorithms for common scaffold alignment, multiple scaffold detection, and scaffold substructure assignment.95 These methods can address the issues of multiple scaffolds, noncommon scaffolds, and symmetrical common scaffolds and produce informative data for structureactivity analysis. Furthermore, the same group described a more informative method for producing
562
r SHENG AND ZHANG
two-dimensional (2D) depiction layout coordinates for each node in a scaffold tree.96 The algorithm includes generating a fragment tree, mapping sibling fragments onto each other in an optimal way, and using this mapping to guide a 2D depiction process. The advantage of the approach lies in that common ancestor fragments can be depicted and oriented in a consistent way and thus common structural features can be readily evident to medicinal chemists. An interactive tool called the scaffold explorer97 differs from other automated scaffold classication algorithms in that the scaffolds can be of arbitrary complexity and the user can construct a scaffold tree interactively. Scaffold explorer allows medicinal chemists to accommodate their intuition and shows good interactivity for mapping SAR across different chemotypes. The above-mentioned methods for building the scaffold trees are mainly based on chemistry-derived rules and are primarily used to map chemical space. If the generation of scaffold trees can be guided by both chemistry and bioactivity-derived rules, chemical space and its related biological space can be navigated with better efciency. Waldmann and colleagues reported an interactive tool, named Scaffold Hunter, for intuitive hierarchical structuring, analysis and visualization of complex structure, and biological activity data.98, 99 Scaffold Hunter reads data containing both chemical structure and biological activity (e.g. data from HTS). Then, the program extracts chemically meaningful scaffolds and iteratively deconstructs those large scaffolds (child scaffolds) one ring at a time to create small scaffolds (parent scaffolds). Biochemical and biological activities were used as major criteria to guide hierarchical arrangement of parent scaffolds and children scaffolds to create a tree with various branches. Thus, the resulting tree can be associated with potency data. The method has been validated by retrospective analysis of two large databases, PubChem and WOMBAT. The advantages of Scaffold Hunter include: (i) it investigates large chemical and biological spaces more rapidly and efciently; (ii) it can identify virtual (or new) scaffolds that possess bioactivity similar to the respective child or parent scaffolds; (iii) it can simplify structurally complex compounds (e.g. natural products) to two-ring to four-ring scaffolds with retained bioactivity that are synthetically tractable and can be used to design new active chemotypes. Figure 3 outlines the process of Scaffold Hunter for identication of new active scaffolds. The seven-ring scaffold 5-lipoxygenase (5-LOX) inhibitor 1 was successively deconstructed one ring at a time.98 A branch of smaller molecules, except 5, were annotated with 5-LOX inhibitory activity in WOMBAT. After testing for 5-LOX inhibitory activity, the three-ring scaffold 5 (IC50 = 9.5 M) and its derivative 8 (IC50 = 3 M) were found to be novel 5-LOX inhibitors. Although they are less active than the four-ring scaffold 3 (IC50 = 1.5 M), compound 5 had higher LE values.100 Moreover, compounds 5 and 8 did not contain typical functional groups found in classical 5-LOX inhibitors and represent a new scaffold for hit optimization. By a similar procedure, a tetrahydroisoquinoline scaffold was identied to possess estrogen receptor (ER ) antagonistic activity,98 and subsequent hit optimization led to novel ligands with a simple two-ring core and good selectivity toward ER (ER ).101
4. ACTIVE SITE MAPPING AND CHARACTERIZATION BY FRAGMENT-BASED APPROACHES An initial step of SBDD is the identication of hot spots in the binding pocket or active site of the drug target. The hot spots (or consensus sites) are important regions that can bind small drug-like molecules and contribute substantially to the binding free energy. Therefore, identication and characterization of such hot spots is critical for rational drug design. Multiple solvent crystal structures (MSCS) is an experimental tool to predict ligand-binding sites of target proteins.102, 103 To use this technique, a crystalline protein is exposed to various organic solvents
r 563
Figure 3. Illustration of the procedure for the generation of the scaffold tree and brachiation-based identication of new active scaffolds for 5-lipoxygenase inhibitors.
(smaller fragments), and then the consensus sites on the proteins surface that are colocalized with multiple solvent molecules can be treated as potential ligand-binding regions. Although MSCS and other experimental methods are efcacious tools for active site mapping, they generally require an expensive investment in equipment and resources. As an alternative, various computational approaches are available to predict the ligand-binding sites of a protein.104 There are two classes of algorithms for structure-based pocket prediction: (i) geometric algorithms and (ii) probe mapping/docking algorithms.105 For the latter, fragments are used as molecular probes for protein surface mapping and identication of hot spots. GRID106, 107 and multiple copy simultaneous search (MCSS)108 are two well-accepted methods for active site characterization. GRID calculates three-dimensional (3D) energy maps around protein binding sites, thus highlighting favorable sites for small functional groups. MCSS randomly places thousands of copies of small functional groups into the binding site, and the most energetically favorable position of each copy is determined by energy minimization. The copies with the
564
r SHENG AND ZHANG
Table I. Summary of Advantages and Disadvantages of Fragment-Based Computational Tools for Active Site Mapping Method GRID CS-Map Advantages Global search of the entire protein surface Better sampling, the ability to nd small buried pockets and desolvation term in the free energy calculation Fast FFT correlation approach to efciently reduce the computational costs The most established method, reasonable use of physicochemical potential functions and incorporation of the standard molecular simulation framework A realistic model including the coexistence of water and revealing the dependence of ligand binding modes on the ligand concentration Fast and simple parameters without prior knowledge and calibration Disadvantages Require empirical parametrization and lack of water molecules in the model No consideration for bonded interactions and different dielectric constants for different targets Lack of water molecules in the model
FTMAP
MCSS
No consideration for the cooperative effects of water and locating minimum enthalpy poses rather than nding hot spots No consideration of protein structural change induced by ligand binding
3D-RISMbased method Grand canonical Monte Carlo simulation Barrils method
Lack of complete validation and case sensitive
Nonparametric and applicable to any target class, and detecting hot spots for both small molecules and macromolecules
Computationally expensive and limited sampling
lowest energies highlight hot spots of ligand binding. The methodology and application of MCSS has been reviewed by Schubert et al.109 Besides GRID and MCSS, other computational approaches based on fragment mapping/docking and scoring are summarized in Table I. Earlier methods in this eld have been reviewed,110, 111 and the following sections mainly focus on important progress in recent years. Vajdas group reported a fragment-based computational mapping program named CSMap.90 CS-Map uses a three-step mapping algorithm81 that includes: (i) nding regions with favorable electrostatics and solvation by rigid body search; (ii) renement of free energy and docking; and (iii) clustering, scoring, and ranking. As compared with earlier mapping methods, CS-Map performs better sampling of regions with favorable desolvation and electrostatics. Its scoring function takes the desolvation effect into account and the positions of the docked ligands are clustered and ranked on the basis of their average free energies. More recently, the same group proposed a new algorithm named FTMAP that uses the Fourier transform (FT) correlation method for sampling proteinprobe complexes in combination with a highly accurate energy function.80 FTMAP is more efcient than CS-Map and free to academic users. A recent validation study revealed that FTMAP could duplicate the MSCS data successfully for two targets of Parkinsons disease.112 Moreover, this method can discover hot spots that are not found in the MSCS experiments. Imai et al. used a 3D reference interaction site model (3D-RISM) to identify the most favorable positions and orientations of fragment molecules on a protein surface.46 A unique feature of the 3D-RISM-based method is that the ligand mapping calculation is performed
r 565
within a realistic model by considering ligands and water at the same level in terms of the site distribution. Therefore, this method may achieve entire ligand mapping on a protein surface in a real solution system. In addition, the 3D-RISM-based method can investigate the inuence of ligand concentration on the binding mode. Some computationally expensive procedures, such as molecular dynamics simulation and Monte Carlo simulation, have also been used for fragment mapping, clustering, and ranking. Clark et al. reported a rapid and practical method to compute binding free energies of a large number of fragment poses on the entire protein surface.113 The method uses grand canonical Monte Carlo (GCMC) simulation to compute ligandprotein binding and predicts the afnities and preferred binding poses of small molecular fragments. Thus, the fragments can be computationally assembled into higher MW lead compounds. Barrils group developed a new method to detect binding sites based on rst-principles molecular simulations.47 Moreover, this method is able to quantify the maximal binding afnity that a ligand may achieve, and thus can efciently measure the druggability of the target. Because the method is not trained on a dataset, it is applicable to any target class. Although it is computationally demanding, it provides very detailed information about the interaction preferences of the binding sites.
5. FRAGMENT DOCKING AND VIRTUAL FRAGMENT SCREENING In most experimental FBDD studies, only hundreds to thousands of fragments can be screened. In contrast, at least 250,000 fragments are commercially available,114 leaving a large portion of fragment libraries untested. Because commercially available fragments are too numerous to be screened experimentally, virtual fragment screening by molecular docking seems to be a complementary approach. However, docking and scoring fragments accurately remains a challenge. First, fragments are small in size and have low MWs. During docking calculations, a number of interaction sites on protein surfaces (closely related energy minima) might be found to accommodate the fragment, which would lead to false docking positions. Even if fragments are placed into the correct pocket, if the binding pocket is large, it might result in incorrect binding modes.115 Second, the internal degrees of freedom of fragments are generally less than larger compounds. It is more difcult to predict their binding pose because alternative binding might yield similar docking scores or calculated binding energies. Third, fragments are always weak binders and current scoring functions are not accurate enough to differentiate an active fragment among many nonactive fragments, because most of the scoring functions have been developed and optimized on the basis of larger drug-like molecules.116 Shoichets group reported pioneering results for fragment docking and screening of AmpC -lactamase inhibitors.117 A database containing 137,639 fragments were docked by DOCK3.5.54. Forty-eight top ranked fragments were subjected to an in vitro enzyme inhibition assay and 23 hits with Ki values in the range of 0.79.2 mM were identied. For AmpC -lactamase, the hit rate of the in silico fragment screening (48%) was considerably higher than both virtual screening and HTS of larger molecules. The accuracy of the docking poses of the active fragments was further investigated by solving the crystal structures of fragment enzyme complexes. For the eight cocrystallized fragments, four fragments had good pose delity and two fragments retained most key interactions (RMSD values: (RMSD range: 1.21.4 A) and 2.6 A). The high hit rate and docking accuracy in this case study supports the 2.4 A feasibility of molecular docking to prioritize molecules from commercially available fragment libraries. Moreover, this study also highlighted the importance of the selection of an appropriate docking method and scoring function. In Shoichets study, DOCK3.5.54 was selected to screen
566
r SHENG AND ZHANG
fragments because its physics-based scoring function can prioritize active fragments from inactive ones.117 In contrast, energy-based scoring functions118 are limited in their applications for ranking fragments. Besides DOCK, several de novo drug design software, such as LUDI107 and SEED,119 also can dock fragments into the correct pocket of the active site. For example, Caischs group developed the program DAIM,102 which can automatically decompose molecules into fragments and then select the anchor fragments for docking. DAIM uses the docking algorithms from SEED103, 119 and has been validated with six different target enzymes.106 Glide120, 121 is another efcient tool for fragment docking.122, 123 Researchers from AstraZeneca evaluated the performance of Glide for virtual screening of fragment inhibitors of DNA ligase and prostaglandin D2 synthase.122 The results indicated that using GlideSP with its default settings gave the best performance and provided an enrichment that was better than random sampling and comparable to virtual screening of drug-like molecules. More recently, evaluation studies suggested that the sampling efcacy of Glide was adequate for fragment docking, but the performance of scoring functions required further improvement.123 Another newly reported study revealed that there is no signicant difference in docking performance between fragments and drug-like compounds.124 Better docking performance was observed for compounds with higher LE values, mainly because they can form high-quality interactions with the target. In 2011, Knehans et al. reported a successful example of in silico fragment screening of dengue virus (DENV) protease inhibitors.125 A library of 149,151 fragments was obtained from RECAP fragmentation of the drug-like molecules from the ZINC database, which were subsequently docked into a homology model of DENV protease by AutoDock Vina.126 A total of 220 top-ranked fragment hits were discovered and subsequently linked to 815 new molecules. Virtual high-throughput docking was performed again to nally select 23 candidates for biological testing and two hits were proven to be active in the micromolar range. It is expected that higher hit rates would be achieved if the accuracy of fragment docking is improved. Regardless, this computational strategy effectively mimicked the process of experimental FBDD, which integrates fragment library design, fragment docking, fragment linking, and biological testing. Two other studies used a similar approach for ligand design,127, 128 but the resulting molecules have not yet been validated by experimental studies. Fragment docking can also be used in parallel to experimental fragment screening. A recent study discovered orally active inhibitors of Hsp90 molecular chaperone by merging structural elements of different hits derived from parallel fragment screening and fragment docking.129 Currently, there are four kinds of strategies to improve the accuracy of fragment docking. The rst is to add sophisticated and intensive computational tools (e.g., MM/PBSA, MM/GBSA, and QM/MM) to the postdocking process. Gleeson et al. evaluated the performance of QM/MM-based models to reoptimize and rescore cross-docking poses of nine fragment-like kinase inhibitors.130 Hybrid QM/MM calculations were proven to be useful as a tool for kinase FBDD. On the contrary, Kawatkars results indicated that adding more computationally intensive procedures to Glide docking, such as MM/GBSA rescoring, did not improve the enrichment.122 Therefore, success with these computationally expensive rescoring strategies might be system dependent. The second strategy to optimize the fragment docking procedure is to improve the performance of scoring functions. The main problem with fragment docking failures is that the scoring functions are often unable to distinguish the correct binding mode from the incorrect ones.124 Marcou et al. found that scoring by the similarity of interaction ngerprints for posing and prioritizing either fragments or molecular scaffolds was statistically superior to conventional scoring functions.131 One possible option to overcome the limitation of scoring functions might be the development of fragment-specic scoring functions.123 To achieve this goal, the binding nature of fragments should be taken into account. For example, fragments
r 567
have less rotatable bonds, hydrogen bond acceptors and donors, and form fewer specic interactions than drug-like molecules. These features should be considered when estimating their enthalpic and entropic contributions during the parameterization of currently available scoring functions. In addition, force eld-based scoring protocols and other more advanced methods for evaluating proteinligand interaction energies are likely to be good solutions for improving fragment-specic scoring functions.124 The third strategy is to make the fragments larger when docking them into the active site. Fukunishi et al. proposed the replica generation (FSRG) method to optimize fragment docking. In the FSRG method, a set of larger molecules (replica molecules) are generated by adding side chains to the fragment. In the docking simulation, only complementarity between the surface of the compound and protein was evaluated, whereas hydrogen-bonding and Coulombic interactions were ignored.132 In a validation study where inhibitors of six target proteins were screened, the FSRG method was proven to be effective in nding active fragments among the decoy compounds. The fourth strategy is to dock multiple fragments simultaneously. In real cases, multiple ligands are always involved in the process of molecular recognition whereas most of the docking methods only dock one ligand at a time. Li et al. proposed the multiple ligand simultaneous docking (MLSD) strategy that can mimic real molecular binding processes and improve the sampling of docking poses and scoring of binding free energy.133 The MLSD method has been used for fragment-based discovery of novel inhibitors of signal transducer and activator of transcription 3 (STAT3).134 A small library of drug scaffolds was simultaneously docked into hot spots of STAT3 by MLSD to identify optimal fragment combinations. Linking of the fragment hits in combination with similarity search and structural optimization led to the discovery of two novel STAT3 inhibitors. Moreover, preparing the protein structure carefully and choosing appropriate parameters are also important for accurate fragment docking.108 Molecular dynamics simulation is an efcient tool to investigate the conformational space of the target proteins and provide reasonable conformation or conformation ensembles for subsequent fragment docking. Ekonomiuks example indicated that using molecular dynamics snapshots of NS3 protease for fragment-based docking could identify two small-molecule inhibitors that could not be identied by simply using the X-ray structure.135
6. FROM FRAGMENTS TO LEADS: DE NOVO DRUG DESIGN A. De novo Drug Design versus FBDD Experimental FBDD uses sensitive biophysical techniques to identify low-afnity fragments hits.4 Then fragment hits are evolved into leads or candidates by various structure-based design strategies.15 In contrast, de novo drug design can be seen as completely virtual FBDD because they have similar concepts and objectives. Both approaches start from small fragments (building blocks) and aim to convert them into drug-like compounds with novel chemotypes and desired pharmacological properties. De novo design was approximately rst introduced in 1989,136 and was regarded as a complementary approach to HTS and FBDD. In principle, de novo design is cost and time effective, and can explore larger chemical space. Although more than 30 de novo design tools have been developed,39, 62 the success of de novo design in lead discovery and optimization lags far behind that of experimental FBDD. With respect to more than ten clinical candidates identied by experimental FBDD,6 de novo drug design rarely generates novel molecules with nanomolar activity. The main problems of de novo design include (i) low efciency in the sampling of the chemical space (or drug-like space); (ii) little consideration for
568
r SHENG AND ZHANG
synthetic feasibility when constructing new structures; (iii) poor accuracy of scoring functions to predict the binding free energy of the designed compounds; and (iv) unreasonable ADME/T properties.39 The success of experimental FBDD greatly motivates the improvement of de novo design. First, the core idea of de novo drug design is very similar to that of experimental FBDD. Developing new methods that can overcome the limitations of traditional de novo design methods should help to nd high quality leads efciently. Second, de novo design could also complement current experimental FBDD methods by providing potential solutions and reducing experimental resources. Third, de novo design tools are helpful to address current challenges of experimental FBDD. For instance, it is difcult to experimentally investigate the linkers that enable fragment hits to maintain their binding mode. In this case, de novo design tools can use simple geometric descriptors to suggest reasonable linkers and predict the binding mode of the resulting molecules by docking and scoring. The starting point for de novo design can be atoms or fragments. It is noted that all the atom-based tools were developed two decades ago.39 Atom-based approaches have the advantage that they can systematically search both the chemical space and structural diversity. However, these tools always suggest a huge number of potential solutions and the resulting molecules are often problematic in terms of chemical stability, synthetic possibility, and drug likeness. These limitations can be overcome by fragment-based approaches because the search space can be signicantly reduced. The synthetic accessibility and drug likeness of the designed ligand can be more readily captured. The typical components of a computational fragmentbased de novo design process include a fragment library, a compound build-up scheme, a scoring function, and an optimization procedure. Table II summarizes the key features of new de novo design methods reported from 2006 to 2011. In the following sections, we will present recent progress made in the methodologies and applications of fragment-based de novo design with a focus on current solutions to address the problems of de novo design.
B. Strategies to Assemble and Optimize Fragments There are two major strategies to assemble fragments into novel molecules: fragment-based growing and/or linking strategies and fragment hybridization strategies. It is estimated that the search space of drug-like molecules is about 1060 compounds, which makes it difcult to evaluate all solutions in a reasonable computational time. Thus, the realistic function of de novo drug design is to efciently nd good solutions rather than nd the best solution. The optimization algorithms can improve the efciency of sampling the huge chemical space of druglike molecules and guide the search to appropriate regions where candidate molecules can be found. Natural Computing algorithms including particle swarm optimization (PSO), evolutionary algorithms (e.g. genetic algorithm, evolution strategy),137 and ant cloning optimization (ACO)138 have been widely used in de novo drug design.139 Such nature-inspired techniques are useful for searching very large chemical space to converge on chemically meaningful optima.
1. Fragment-Based Growing and Linking Strategies For the growth approaches, predened conformation between a seed (xed scaffold) and the binding pocket of the receptor is necessary. The binding complex can be obtained from molecular docking or experimental techniques. Then, the seed grows fragment by fragment to complement the active site geometrically and energetically. At each step of fragment growth, scoring functions are used to accept or reject the modications. Early methods of this type include: SmoG,140, 141 GrowMol,142 GroupBuild,143 SPROUT,144 and GROW.145

Table II. Important Features of the De Novo Design Methods Reported from 2006 to 2011. Methods Fragment hopping Building blocks Five general-purpose libraries: the basic fragment library, the bioisostere library, the rules for metabolic stability, the toxicophore library, and the side chain library Filtering the ZINC database by atom numbers Pseudoretrosynthetic fragmentation of six compound libraries Assembly rules Fragment linking by LUDI Search procedure Mapping fragments on the minimal pharmacophoric elements
r 569
Fitness functions Consensus docking scoring, ADMET lters
AutoGrow
COLIBREE
Fragment-based growing strategies A xed build-up scheme of scaffold, linkers, and building blocks Sequential growth strategy, consider synthetic possibility by well-dened connection rules A restricted set of reaction schemes The sequential growth of small molecules constrained by the transition probabilities of the growth fragment Incremental construction of novel ligands
Evolutionary algorithms A discrete version of particle swarm optimization (PSO) Incremental construction algorithm within FlexX
AutoDock scores
FlexNovo
Large fragment spaces with up to several thousand fragments
Using CATS topological pharmacophore similarity to reference ligands as tness function Scoring functions from FlexX, physicochemical property lters, pose geometry, and diversity lter Ligand-based similarity scoring using reference compound A linear scoring algorithm (TopClass)
Flux
Virtual retrosynthesis of the COBRA dataset by RECAP Collection of connectivity statistics for fragments of interest from a database of small molecules
Evolutionary algorithms
FOG
Statistically biasing the growth of molecules with desired features
Fragment shufing
GANDI
Alignment of the proteinligand complexes, ligand fragmentation, and calculation of fragment score Fragment library from molinspiration cheminformatics
A tree search algorithm
QXP scores together with the overall fragment scores
Linking predocked fragments by SEED
A genetic algorithm and a tabu search
A linear combination of three scoring functions including force eld energy and 2D or 3D similarity
570
r SHENG AND ZHANG

Methods Building blocks Using MED-SuMoFragmentor to dene 3D proteinfragment patterns called MED-Portion Assembly rules Recombining chemical moieties from MED-Portions into putative ligand molecules Search procedure Query MED-SuMo database Fitness functions MED-SuMo hit descriptors, bioinformatic descriptors, and physicochemical properties; target-specic lters for hybridized molecules Binding afnity scorers, molecular similarity scorers, and chemical structure scorers
Table II. Continued
MED-Hybridise
MEGA
SQUIRRELnovo
Hechts method
Recore
EAISFD
LigBuilder 2.0
A substructure mining tool including frequent subgraph mining and RECAP rule Multiconformer database (17,934 fragments) by RECAP-based fragmentation of COBRA collection Fragmentation of literature libraries into scaffolds and R-group fragments Fragmentation of CSD database by RECAP rules and ltered by various criteria A fragment library with over 1300 fragments extracted from MDDR Extraction from WDI database
Growing strategy
Combines multiobjective evolutionary techniques with graph theory
Bioisosteric replacements
Alignment of fragments to a reference compound by graph matching algorithm Evolved fragment assembly
LIQUID fuzzy pharmacophore function
Fragment linking and docking
Binding afnity score and articial neural network
Scaffold replacement
R-tree index and k-nearestneighbor search Evolutionary algorithm
Geometric ranking
Scaffold hopping or substructure optimization
Surex-Dock score
Growing and linking
Genetic algorithm
Binding afnity prediction, physicochemical properties evaluation, lockkey match evaluation, synthesizability prediction

Table II. Continued Methods NovoFLAP Building blocks A fragment library with over 1300 fragments extracted from MDDR 594 fragments derived from decomposition of Thomson Pharma database Assembly rules Modication or hopping of the starting structure Search procedure Evolutionary algorithm (EA-Inventor)
r 571
Fitness functions Ligand-based scoring function: exible ligand alignment protocol (FLAP) PROTOSCORE that includes improved terms for the estimation of entropy plus terms for various nonbonded interactions Fitness score to the pharmacophore hypothesis, assessment of drug likeness, and synthetic accessibility
PROTOBUILD
Fragment growth in the binding site according to a set of fragment fragment interconnectivity rules Linking fragments that are tted to pharmacophore model
Genetic algorithm
PhDD
Eight types of fragment databases (correspond to eight popular pharmacophore features) by fragmentation of MDDR and CMC
Alignment of fragments to the pharmacophore hypothesis
Fragment-based growing strategies are computationally efcient and the generated molecules always have good chemical diversity. Moreover, the growth methods always combine docking software for binding pose prediction and scoring. For example, the incremental construction algorithm of docking software FlexX146 was used to develop the new de novo design algorithm FlexNovo.147 FlexNovo works with the fragments directly and deals with large fragment spaces (several thousand fragments). Moreover, various lters including physicochemical properties, diversity, and placement geometry have been incorporated into the fragment build-up process. More recently, FlexNovo was implemented into a comprehensive project named NovoBench.148 The NovoBench project integrates several tools, such as generation of fragment space (Colibri149 and FragView), structure-based (FlexNovo147 ), property-based (FragEnum150 ), and ligand-based (Ftrees-FS64 ) search algorithms to meet the various demands of de novo design. In many growing strategies, the binding mode or pose of the seed fragment is assumed to be xed upon fragment growth. However, this assumption is often invalid in many cases. Durrant et al. developed AutoGrow that combines elements of fragment-growing, docking, and evolutionary algorithm.151 In AutoGrow, each generated new compound during fragment addition is dynamically redocked into the binding pocket by AutoDock152 and generates new poses for each molecule. An evolutionary algorithm is used to explore new chemical space by evaluating the docking scores of every population member, and select the best molecule for subsequent generation. Another method, FOG, also grows molecules by adding fragments to a nascent molecule.153 The novelty of FOG lies in that the growth of molecules depends on the frequency of specic fragmentfragment connections by mining a specic molecular database. In addition, FOG can be trained to grow new molecules with chemical and topological features similar to a desired
572
r SHENG AND ZHANG
class of compounds (e.g. natural products and drugs) by the Topology Classier (TopClass) algorithm. Fragment-based linking strategies map fragments onto the key regions in the binding pocket to determine various energetically favorable positions and then link them together to build new molecules. The above-mentioned active site mapping approaches, such as GRID and MCSS, are commonly used to position seed fragments or functional groups to the correct locations in the binding pocket. The link concept has been widely used in a number of de novo design methods including CONCERTS,154 LUDI,155, 156 CAVEAT,157 NEWLEAD,158 DLD,159 BUILDER,160 and SKELGEN.161 These methods can search large chemical space using a relatively small number of initial fragments. The resulting molecules are expected to bind more tightly with the target than the individual fragment. However, fragment linking might lead to a change of the overall conformation of the generated molecules, and key interactions between the initial fragment and target might be lost. Thus, redocking the new ligands might be necessary in the postprocessing step. GANDI is a new de novo design tool for automatically linking predocked fragments with a user-dened fragment library.162 GANDI uses SEED163 for fragment docking and its optimization procedure combines a genetic algorithm and a tabu search. An important feature of GANDI is its multiobjective evolutionary optimization strategy that simultaneously optimizes the force eld energy and a 3D-overlap term to known binding modes or a 2Dsimilarity term to known inhibitors. Thus, GANDI can be both structure-based and ligandbased according to the users need. In addition, GANDI is free to academic users, which provides more opportunities to validate the method. Ji et al. proposed fragment hopping as a new fragment-based tool for de novo inhibitor design.164, 165 Fragment hopping is a pharmacophore-driven strategy focusing on isozyme selectivity and ligand diversity. The derivation of the minimal pharmacophoric element for each pharmacophore is the key point of this approach. The minimal pharmacophoric element can be an atom, a cluster of atoms, a virtual graph, or vector(s), which can be derived from a combinatorial application of different active site analysis and pharmacophore identication methods. The novelty of minimal pharmacophoric elements lies in that they can map an important interaction pattern between a ligand and hot spots for both isozyme selectivity and ligand binding based on a priori knowledge and experience. Five fragment libraries are implemented within fragment hopping. The basic fragment library and the bioisostere library are queried to generate a focused fragment library with diverse structures that can match the requirements of the minimal pharmacophoric elements. Then, the focused fragment library is ltered by the rules for metabolic stability and the toxicophore library. The binding positions of the resulting fragments to each pharmacophore are searched by LUDI and the MCSS program. Finally, the desired molecules are generated by linking these fragments using the side chain library. The evaluation process includes docking, consensus scoring, and ADMET lters. Moreover, this new de novo design methodology is an open and interactive system according to the medicinal chemists requirements for a specic research project. The application of fragment hopping to de novo design of highly potent and selective neuronal nitric oxide synthase (nNOS) inhibitors will be introduced in the section of case studies. More recently, Lais group developed LigBuilder 2.0,166 which is an improved version of their previously reported method LigBuilder 1.0.167 LigBuilder uses a genetic algorithm to construct ligands iteratively by fragment linking or growing. Compared with LigBuilder 1.0, the new version takes synthetic accessibility into account by an embedded chemical reaction database and a retrosynthesis analyzer (SYLVIA).168 Moreover, an accurate cavity detection program (Cavity 1.0) and the Drug Space Exploring Algorithm was incorporated into the design process. Various lters including binding afnity evaluation, physicochemical properties evaluation, and lock-key match evaluation are used to nd the best molecules.
r 573
2. Molecular Hybridization and Scaffold Hopping Molecular hybridization is a common design strategy in medicinal chemistry.169, 170 The core idea of molecular hybridization is to combine pharmacophoric fragments from different bioactive compounds to generate a new hybrid molecule with improved biological or physicochemical properties. This concept has been used to develop new de novo design algorithms. BREED is the rst automated method that produces novel molecules from structures of different known ligands targeting a common receptor.171 This method takes advantage of the structural information of known ligandstarget complexes, aligns the 3D coordinates of two ligands, and recombines fragments at overlapping bonds to generate hybrid molecules. Inspired by the idea of the BREED method, Wangs group developed an automatic method named automatic tailoring and transplanting (AutoT&T) that can effectively utilize the results of virtual screening in fragment-based lead optimization.172 AutoT&T identies suitable fragments from virtual screening hits and then transplants them onto a predened lead compound to generate new ligand molecules with improved binding afnities. As compared with the conventional de novo design methods, AutoT&T has several advantages. First, it detects fragments directly from other organic molecules and does not rely on a predened building block library. The input molecule databases can be exible with no limitations in terms of sizes or types. Second, AutoT&T is more efcient and does not have the problem of combinatorial explosion. It performs structural transplantation on the basis of the matched bonds between the lead compound and each given steak molecule without adopting a sequential build-up approach. Third, synthetic feasibilities and drug-likeness properties are taken into account during the invention of new molecules. The idea of mix and match in BREED was also used to develop several new algorithms, such as MED-Hybridise and fragment shufing. Fragment shufing differs from BREED in the way that it is able to hybridize multiple ligands within one iteration step and includes fragment scores to guide the incremental construction of the new ligands.173 MED-Hybridise is a computational drug design toolkit at PDB scale that combines the local similarity of protein surfaces and a fragment-based approach.174 MED-Hybridise takes advantage of the rich structural information of targetligand complexes in the PDB database. An important step in MED-Hybridise is to dene the MED-Portion, which is the 3D protein-fragment patterns obtained from mining all available proteinligand crystal complexes within a library of small molecules. For any binding surface query, matched MED-Portions can be retrieved using MED-SuMo175, 176 to superimpose similar protein interaction surfaces. The resulting MEDPortion chemical moieties are collected and used to generate new 3D hybrid molecules. In a retrospective validation study, MED-Hybridise could successfully retrieve scaffolds of known active compounds for a GPCR target ( 2-adrenergic receptor) and a protein kinase target (vascular endothelial growth factor receptor 2, VEGFR-2). The concept of scaffold hopping177 is similar to that of molecular hybridization. The core idea of scaffold hopping is to replace a central element of the molecular scaffold by a new molecular fragment. There are several computational tools for scaffold hopping.178 Recore is a fast and effective approach for scaffold replacement that uses 3D fragments as queries and can search pharmacophore-type features.179 Moreover, Recore incorporates k-nearest-neighbor searches and a voting system to enable the exploration of large search spaces. 3. Ligand-Based Methods Although the majority of de novo design tools are structure-based methods, they also face several major challenges such as the accuracy of the scoring functions and the exibility of the
574
r SHENG AND ZHANG
receptor. Moreover, it remains a challenge to solve the crystal structures of many membranebound drug targets (e.g. GPCRs). In this case, ligand-based methods provide an alternative for de novo drug design. Such approaches do not rely on the 3D structure of the drug target and instead, their design process is guided by maximizing the similarity between the generated molecules and the known active compounds. Ligand-based methods are an emerging hot area in recent years. Schneiders group has proposed three promising approaches (i.e. COLIBREE, Flux, and SQUIRREL).62, 180 COLIBREE uses a xed build-up strategy by adding various building blocks and linkers to a predened molecular scaffold to generate a focused combinatorial library.181 The optimization procedure is guided by a stochastic optimization algorithm, PSO,180 with CATS topological pharmacophore similarity177 to reference ligands as a scoring function. Flux assembles molecules by a restricted set of reaction schemes and the chemical synthesis of the constructed molecules is eased using molecular building blocks obtained from the RECAP principle.182, 183 A stochastic search algorithm is implemented in Flux with similarity-based descriptors and metrics as tness functions. SQUIRREL is a new algorithm to compare both molecular shape and potential pharmacophore features.184 It was used to develop a ligandbased de novo design tool that can suggest bioisosteric replacement groups for a reference compound.185 Triposs EA-Inventor is a generic structure invention engine based on an evolutionary algorithm.186 It works on the connection tables of an initial population of structures and the evolutionary process of structure invention. It can be driven by any user-dened scoring function (binding afnity, pharmacophores, similarity, or other desired properties). EA-Inventor has been used in several structure-based or ligand-based de novo design approaches.187190 Liu et al. reported a structure-based method named EAISFD,189 which combines EA-Inventor for structure evolution with Surex-Dock191, 192 for docking and scoring. EAISFD introduced the Tagged Fragment (TF) strategy for the multiobjective build-up process. TF can be either a fragment (substructure) of the ligand or a new fragment attached to the ligand that serves to anchor key binding interactions. Thus, the TF strategies can be used for partial or full drug design, such as scaffold hopping, substructure optimization, and structure extension. Now, EAISFD has been developed into a commercialized product, namely Muse (http://www.tripos.com), for de novo drug design. More recently, researchers from Tripos reported NovoFLAP as a ligand-based approach that combines EA-Inventor with a powerful scoring function Flexible Ligand Alignment Protocol (FLAP). FLAP uses both molecular shape and pharmacophoric features in a multiconformational context.187 Pharmacophore hypothesis can also be useful in de novo drug design. Fragments that t in different parts of a pharmacophore model can be linked together by various spacers to generate novel structures. NEWLEAD is the rst pharmacophore-based de novo design method.158 However, it can only process pharmacophoric functional groups rather than abstract chemical features such as hydrogen bond donors and acceptors, and hydrophobic features. Yangs group made important improvements for pharmacophore-based de novo design. Their new method, PhDD, is able to work with abstract pharmacophore models and be implemented with comprehensive evaluators including drug likeness, bioactivity, and synthetic accessibility.193 A research group from Eli Lilly reported a fragment-based method for the de novo design of kinase inhibitors.194 Fragmentation of existing kinase inhibitors was used to generate building blocks that were subsequently recombined to create de novo chemical libraries. The libraries were driven by a general kinase pharmacophore model and a support vector machine based method (SVMFP)195 was used to predict combinations of fragments. The overall hit rate of the pharmacophore-driven de novo library was very high (92%), which highlights the superiority of this fragment-based strategy over virtual screening or structure-based minor modications of existing inhibitors.
FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD C. Scoring Functions and Multiobjective Optimization
r 575
Scoring functions are crucial to guide the optimization process and to evaluate the binding afnity or chemical similarity of the designed molecules. During the process of sampling chemical space, a huge number of iterations should be evaluated by a scoring function. Thus, scoring functions are required to be fast, but this feature comprises their accuracy. Scoring functions from molecular docking are popular in structure-based de novo methods.196 These scorers are adept at discriminating between inactive and active compounds, but their ability to rank the ligands with similar chemotypes is relatively poor. Therefore, the application of docking-based scoring functions in de novo design is less successful than in virtual screening. On the other hand, comprehensive physics-based approaches, such as MM-GBSA/PBSA,197, 198 free-energy perturbation,199, 200 single-step perturbation,201 GCMC simulations,113 and thermodynamic integration,202 can yield very accurate binding free energies. However, these methods require high computational expenses, and thus are not suitable for the search process of de novo design. Even so, they are very helpful to improve the success rate of de novo design by re-evaluating the nal molecules after postprocessing and identifying the best one for chemical synthesis and biological testing. Nowadays, the availability of computational resources (e.g. cloud computing) is increasing dramatically, which will enable a wider use of physics-based scoring functions in de novo design. Computational intelligence, such as machine learning approaches, has been used in drug design for the automatic selection of important features and the optimization of models.203 In combination with traditional scoring functions, computational intelligence tools can quickly and efciently search diversity space for good solutions. Hechts method uses an evolved fragment assembly algorithm for directed searches of novel leads.204 The novelty of the method lies in that it uses a computational intelligence screening tool for compound selection. The screening tool integrates evolved articial neural nets, docking software as well as QSAR and QSPR models. Early de novo design approaches have been created to satisfy a single objective and most of them have focused on the interaction scores with the binding pocket. However, these methods ignore the multiobjective nature of drug discovery and development. Thus, the application of multiobjective optimization strategies in design workow is benecial to improve the drug-like behavior of the generated molecules. Moreover, multiobjective optimization methods can avoid local optima and dead ends corresponding to a single objective and lead to a more efcient search process. MEGA is a new de novo design algorithm for multiobjective optimization that combines graph theory with evolutionary techniques to perform an efcient global search for promising solutions.205 Three kinds of tness functions, namely binding afnity scorers, molecular similarity scorers, and chemical structure scorers, are used to guide the optimization process. Therefore, structurally diverse molecules with good binding energy and drug-like properties can be designed by MEGA.
D. Synthetic Accessibility and Drug Likeness Synthetic accessibility is one of the key issues that remain to be addressed in de novo design. Two types of approaches have been reported to improve the synthetic accessibility of computerdesigned structures. The rst approach uses connection rules and synthesizable building blocks to construct new molecules. Synthesizable building blocks can be obtained either from decomposition of compound databases by virtual retrosynthesis rules or from commercially available compounds. The connection rules are mainly derived from organic synthesis reactions.206, 207 As mentioned above, RECAP59 rules have been commonly used to disassemble and reconstruct synthetically feasible molecules (e.g. TOPAS206 and Flux). The advantage of using RECAP
576
r SHENG AND ZHANG
rules in de novo design is that the chemical environment around a new bond is similar to that in drug-like and synthesizable compounds. Compounds created from such rules are more approachable. The limitations of RECAP lie in that they are crude abstractions of actual chemical reactions and only cover a small number of types. Moreover, compounds constructed from RECAP rules are only potentially synthesizable, and no scores and synthetic routes can be suggested. Other methods, such as SYNOPSIS,207 use known chemical reactions to form bonds between readily available building blocks. A total of 70 selected organic reactions were implemented in SYNOPSIS and the building blocks are taken from the ACD208 database. The second approach is amenable to the rst one and uses additional scoring functions to evaluate the synthesizability of the generated candidates in the postprocessing step. For example, FOG generates synthetically tractable molecules by use of the software168 SYLVIA.153 Other computer-aided organic synthesis design methods, such as Route Designer,209 can suggest synthetic routes for experimental validation studies of de novo design. More recently, new cheminformatics tools (e.g. reaction vectors210 and Reaction-MQL211 ) for the representation and encoding of organic reactions should contribute to the de novo design of molecules with good synthetic accessibility. A new algorithm named DOGS is under development by Schneiders group.62, 212 DOGS is based on a series of known reactions selected from the literature and can propose at least one possible synthetic route for each designed compound. Other methods for synthetic evaluation are reviewed by Kutchukian et al.213 Drug likeness is another important constraint in de novo design. As described above, the consideration of drug likeness has been incorporated into every stage of de novo drug design. The fragment libraries for molecular invention are often obtained from the decomposition of a drug or drug-like database, which is based on the assumption that molecules built from drug-like building blocks are more likely to possess drug-like properties. An efcient search of drug-like chemical space is also necessary to invent high-quality molecules. In the postprocessing stage, Lipinskis rule of ve214 is used as a popular lter for prioritizing candidates before synthesis and biological evaluation. Moreover, recent progress in computational ADMET prediction strategies215 can also be applied to de novo drug design, which is helpful to re-evaluate the candidate molecules in a cost-effective manner.
E. Recent Examples of Fragment-Based De Novo Design Although de novo design tools are far from perfect and rarely generate ligands with nanomolar activity, they can be viewed as an idea generator to provide novel chemotypes for medicinal chemists.196 Integration of de novo design software and expertise knowledge of medicinal chemists is likely still necessary to nd high-quality hits or leads. Table III summarizes recent examples of de novo design.216233 In combination with our own work in this eld, four successful examples will be discussed in detail. 1. Case 1: De Novo Design of Selective nNOS Inhibitors NOS represent a family of enzymes that produces nitric oxide (NO). There are three isozymic forms of NOS including endothelial (eNOS), macrophage or inducible (iNOS), and neuronal (nNOS) isozymes. Among them, nNOS is an important target for various neurodegenerative disorders.234 However, structure-based design of isoform-selective inhibitors is a difcult and challenging task because the active sites are nearly identical for all three NOS isoforms.235238 Ji et al. reported successful examples for the de novo design of selective nNOS inhibitors on the basis of the minimal pharmacophoric elements and fragment hopping.164 The active site of NOS was investigated by two different methods (i.e. GRID and MCSS) and the obtained information combined with previous SAR results led to the generation of the minimal pharmacophoric

Table III. Selected Examples of Fragment-Based De Novo Design from 2006 to 2011
r 577
578
r SHENG AND ZHANG
Table III. Continued

Table III. Continued
r 579
580
r SHENG AND ZHANG
Figure 4. A Minimal pharmacophoric elements for selective nNOS inhibitor design. B Binding mode of inhibitor 9 with nNOS and hydrogen bonds are displayed as red dash lines. C Chemical structures of two novel nNOS inhibitors derived by fragment-based de novo design. The structural information is obtained from the Protein Databank (PDB code: 3B3N).
elements for nNOS. The minimal pharmacophoric elements identied for selective nNOS inhibitor design included an amidino group, four nitrogen atoms, and two hydrophobic (or steric) groups (Fig. 4A). An amidino group is positioned close to E592 of nNOS to form chargecharge and hydrogen-bonding interactions. A sp3 -hybridized nitrogen cation is placed close to the selective region dened by D597, while the other three nitrogen atoms are near to the heme propionate to form chargecharge interactions and hydrogen bonds. The regions where hydrophobic and/or steric interactions play important roles are the positions closest to D597 and the heme propionate. Using a design process of fragment hopping, a focused fragment library was generated to match the minimal pharmacophoric elements and the fragments were linked by LUDI to build new molecules. After evaluation, compound 9 (Fig. 4C) and its analogues were subjected to chemical synthesis and inhibitory activity testing. Compound 9 revealed potent inhibitory activity toward nNOS (Ki = 388 nM). Moreover, it was also a highly selective nNOS inhibitor with 1100-fold and 150-fold selectivity over eNOS and iNOS, respectively. The crystal structure of nNOS in complex with compound 9 indicated that only the (3 S, 4 S)-isomer was bound and its binding conformation was similar to that obtained from docking. The nitrogen atom of the pyrrolidine ring interacted with the region for selectivity, which is lined with residues nNOS Asp597/eNOS Asn368 (Fig. 4B). The nitrogen atom next to the pyrrolidine ring formed a hydrogen-bonding interaction with one of the heme propionate groups and the terminal amino group formed chargecharge and hydrogen-bonding interactions with the heme propionate of the pyrrole D ring and one structural water.
r 581
Although compound 9 is a selective inhibitor of nNOS, it is too hydrophilic to cross the blood-brain barrier. Subsequent optimization studies were focused on increasing its inhibitory activity and lipophilicity.165 Two hydrophobic/steric pockets of nNOS were identied by fragment hopping, which were used to generate minimal pharmacophoric elements for better ligand potency as well as better physicochemical and pharmacokinetic proles. After introducing a methyl group on the 2-aminopyridine ring and a substituted phenylethyl group on the terminal amino group, compound 9 was evolved into 10, which formed stronger hydrophobic interactions with these two pockets. Compound 10 showed higher inhibitory potency for nNOS compared to 9. The Ki value for the racemic mixture was 14 nM, and its nNOS selectivity over eNOS was 2000-fold. Further studies revealed that (3 R, 4 R)-10 showed better activity and selectivity than the other isomers.239 The Ki value for (3 R, 4 R)-10 with nNOS was 5.3 nM and its selectivity of nNOS over eNOS and iNOS was more than 3800-fold and 700-fold, respectively. Moreover, a racemic mixture of compound 10 also showed good in vivo efcacy in a rabbit model for cerebral palsy.240 This study also validated the ability of fragment hopping to achieve better inhibitory potency and isozyme selectivity, which are important aspects for lead optimization. 2. Case 2: De Novo Design of Small Molecule Inhibitors of Cyclophilin A Cyclophilin A (CypA) plays an important role in numerous biological processes.241243 Small molecule CypA inhibitors can be used for developing immunosuppressive, antitumor, and cardiovascular agents. Lis group found that the amide fragment is an important pharmacophore for CypA inhibitors. The amide group functions as the key linker between two terminal fragments and interacts with the saddle between two sub-binding pockets of CypA. On the other hand, the urea fragment has also been used as a linker for CypA inhibitors.244 By fusing amide and urea, a new linker, acylurea, was designed as the seed for de novo drug design (Fig. 5A).245 Using LigBuilder 2.0,166 the seed structure grew from both ends to t the shape and properties of the two sub-binding pockets in CypA (Fig. 5B). The generated molecules containing different R1 and R2 fragments were ranked according to the scores of binding afnity, biological availability, shape complementarity, and synthesizability. Finally, compound 11 was chosen for chemical synthesis and was proven to be a highly potent CypA inhibitor (IC50 = 31.6 2.0 nM). Subsequent SAR studies revealed that the placement of the 9H-uorene ring by other aromatic groups was not tolerated. The optimization of the 2,6-dihyroxy substituents yielded a more potent inhibitor (compound 12, IC50 = 1.52 0.1 nM). Figure 5C depicts the binding mode of compound 11 with CypA. The planar uorene ring and 2,6-disubstituted phenyl moiety t two hydrophobic areas in site A and B, respectively (Fig. 5C). The acylurea linker formed seven hydrogen bonds with residues Arg55, Gln63, and Asn102 in the saddle site. In particular, compound 12 represents the most potent CypA inhibitor reported to date. 3. Case 3: Optimization of 5-HT1B Receptor Antagonists by a Ligand-Based De Novo Design Method Besides generating entirely novel molecules, de novo design can also be used to modify existing structures. A research group from AstraZeneca reported a successful story of lead hopping and optimization of 5-HT1B receptor antagonists using the ligand-based de novo design tool NovoFLAP (Fig. 6).246 Based on the chroman template 13, a library was generated and ranked by NovoFLAP by focusing on the replacement of the basic piperazine moiety. Pyrazole-based compound 14 was initially selected because of its potential ability to form hydrogen-bonding interactions with an aspartic acid residue of the 5-HT1B receptor. After taking chemical accessibility into account, a small library of pyrazolequinolone derivatives was synthesized. Compound 15 was the most potent ligand toward the 5-HT1B receptor (Ki = 9.3 nM), but it
582
r SHENG AND ZHANG
Figure 5. A The process of fragment-based de novo design of novel CypA inhibitors. B The general binding pattern of CypA inhibitors. C The binding mode of novel inhibitor 11 with CypA.
Figure 6.
Optimization of 5-HT1B receptor antagonists by the ligand-based de novo design tool NovoFLAP.
r 583
was found to be a partial agonist. Subsequent optimization efforts led to the discovery of compound 16 as a full antagonist, which showed improved activity with a highly selective prole (Ki = 0.43 nM). Moreover, compound 16 showed a dose-dependent reversal of agonist-induced hypothermia in an in vivo model. The new series obtained from de novo design represent the rst nonbasic (without the ubiquitous piperazine moiety) antagonists of the 5-HT1B receptor. This example also reveals the promise of de novo design for lead optimization. 4. Case 4: Fragment-Based De Novo Design and Optimization of CYP51 Inhibitors Lanosterol 14 -demethylase (CYP51) is an important antifungal target. Triazole antifungal drugs (e.g. uconazole and voriconazole) are classical CYP51 inhibitors and are used as rstline antifungal agents. 3D models of fungal CYP51s have been constructed by our group using comparative homology modeling.247249 On the basis of the CYP51 models, computational fragment-based methods have been applied to optimize triazole antifungal agents and design novel CYP51 inhibitors.250 With an aim to nd highly potent and broad spectrum triazole antifungal agents, our group proposed a fragment-based pharmacophore model to improve the efciency of azole optimization (Fig. 7).251 In this model, four kinds of functional fragments including linker, aromatic or alkyl group, hydrogen bond acceptor, and hydrophobic group were discovered as important for CYP51 binding and antifungal activity. Various functional fragments have been designed and combined to t the model (Fig. 7), and most of the resulting compounds showed good antifungal activity against clinically important pathogenic fungi.252258 Several new triazole derivatives showed better activity than itraconazole and uconazole with minimum inhibitory concentration (MIC) values ranging from 0.25 g/mL to 0.001 g/mL. Among the highly active triazoles, a promising candidate named iodiconazole was selected for drug development and is currently in a phase III clinical trial.259261 Our group has used fragment-based methods for the de novo design of novel CYP51 inhibitors that are expected to overcome the cross-resistance and hepatic toxicity of triazole antifungal agents.262 The active site of CYP51 was explored by MCSS and the key regions essential for inhibitor binding were identied. Various MCSS minima were linked to a benzopyran scaffold by LUDI to afford a series of new inhibitors. Compound 17 had an IC50 value of 35.21 M toward Candida albicans CYP51 (Fig. 8) and represents a good lead for further optimization. Extensive scaffold hopping studies have been performed to nd a better core fragment (Fig. 8).263266 The aminotetralin scaffold and benzoimidazole scaffold were also found to be favorable for the antifungal activity.263, 266 Because these novel inhibitors do not coordinate with the heme and interact with CYP51 mainly through nonbonding interactions, they are promising leads for the development of selective antifungal agents with better safety proles.
7. CONCLUSIONS Considerable developments have been made in the methodology and application of FBDD over the past 15 years. Despite these successes, experimental FBDD requires high-quality protein, highly soluble fragments, expensive detection equipment, and specic expertise, which limit its applications to selected laboratories and biological targets. In this context, cheminformatics and computational chemistry can be used as alternative approaches. Computational approaches can play a synergistic role in each step of experimental FBDD by maximizing its performance. Computational FBDD can also be used independently in generation and optimization of leads. In particular, fragment docking and de novo design methods have been widely used, but there are limited good examples. Even so, rapid progress has been made in these elds and successful examples are emerging.
584
r SHENG AND ZHANG
Figure 7.
Fragment-based optimization of triazole antifungal agents.
In order to improve the efciency and applications of FBDD, future research should be focused on methodology development and integration. For experimental FBDD, the methodologies are required to be continually developed, and includes the construction of improved fragment libraries that cover larger drug-like space, the development of higher throughput, and more sensitive biophysical methods for fragment screening and the improvement of strategies for evolving fragments into leads. For computational FBDD, it is of key importance to develop new methods that can accurately predict the binding pose of fragments and estimate the binding free energy (both entropy and enthalpy predictions). Although such developments are also challenging for current computer-aided drug design methods, the accuracy of computational FBDD needs to be at least comparable to those of drug-like molecules. De novo design has
r 585
Figure 8. De novo design of novel CYP51 inhibitors by MCSS/LUDI and the optimization of the core fragment by scaffold hopping.
great potential for both inventing novel structures and optimizing existing leads. Inspired by the success of FBDD, rapid progress has been made in the methodologies of de novo design in the last 5 years. Although it is still lacks effectiveness, de novo design is expected to be developed into a routine tool for drug discovery and attract wider acceptance by medicinal chemists. A major weakness of de novo design is its poor ability in scoring and the prediction of binding energies. New scoring functions should help to achieve a balance of accuracy and speed. Taking the advantages of both experimental and computational FBDD and combining them into an integrated drug design process will maximize the efciency of drug discovery. With the development of both experimental and computational FBDD technologies to address these challenging problems, FBDD should become accessible to both academia and the pharmaceutical industry, and promote drug discovery at a faster pace.
ACKNOWLEDGMENTS We gratefully acknowledge nancial support from the National Natural Science Foundation of China (Grants 30930107 and 30973640), the 863 Hi-Tech Program of China (Grant 2012AA020302). Shanghai Municipal Health Bureau (Grant XYQ2011038), and Key Laboratory of Drug Research for Special Environments, PLA.
REFERENCES
1. Mayr LM, Bojanic D. Novel trends in high-throughput screening. Curr Opin Pharmacol 2009;9:580 588. 2. Bohacek RS, McMartin C, Guida WC. The art and practice of structure-based drug design: A molecular modeling perspective. Med Res Rev 1996;16:350. 3. Gribbon P, Sewing A. High-throughput drug discovery: What can we expect from HTS? Drug Discov Today 2005;10:1722. Medicinal Research Reviews DOI 10.1002/med
586
r SHENG AND ZHANG
4. Hajduk PJ, Greer J. A decade of fragment-based drug design: Strategic advances and lessons learned. Nat Rev Drug Discov 2007;6:211219. 5. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. Discovering high-afnity ligands for proteins: SAR by NMR. Science 1996;274:15311534. 6. Chessari G, Woodhead AJ. From fragment to clinical candidateA historical perspective. Drug Discov Today 2009;14:668675. 7. Schuffenhauer A, Ruedisser S, Marzinzik AL, Jahnke W, Blommers M, Selzer P, Jacoby E. Library design for fragment based screening. Curr Top Med Chem 2005;5:751762. 8. Siegal G, Ab E, Schultz J. Integration of fragment screening and library design. Drug Discov Today 2007;12:10321039. 9. Lepre CA, Moore JM, Peng JW. Theory and applications of NMR-based screening in pharmaceutical research. Chem Rev 2004;104:36413676. 10. Swayze EE, Jefferson EA, Sannes-Lowery KA, Blyn LB, Risen LM, Arakawa S, Osgood SA, Hofstadler SA, Griffey RH. SAR by MS: A ligand based technique for drug lead discovery against structured RNA targets. J Med Chem 2002;45:38163819. 11. Erlanson DA, Wells JA, Braisted AC. Tethering: Fragment-based drug discovery. Annu Rev Biophys Biomol Struct 2004;33:199223. 12. Hartshorn MJ, Murray CW, Cleasby A, Frederickson M, Tickle IJ, Jhoti H. Fragment-based lead discovery using X-ray crystallography. J Med Chem 2005;48:403413. 13. Danielson UH. Fragment library screening and lead characterization using SPR biosensors. Curr Top Med Chem 2009;9:17251735. 14. Neumann T, Junker HD, Schmidt K, Sekul R. SPR-based fragment screening: Advantages and applications. Curr Top Med Chem 2007;7:16301642. 15. Rees DC, Congreve M, Murray CW, Carr R. Fragment-based lead discovery. Nat Rev Drug Discov 2004;3:660672. 16. Flaherty KT, Yasothan U, Kirkpatrick P. Vemurafenib. Nat Rev Drug Discov 2011;10:811812. 17. Murray CW, Rees DC. The rise of fragment-based drug discovery. Nat Chem 2009;1:187192. 18. Congreve M, Chessari G, Tisi D, Woodhead AJ. Recent developments in fragment-based drug discovery. J Med Chem 2008;51:36613680. 19. Zartler ER, Shapiro MJ. Fragonomics: Fragment-based drug discovery. Curr Opin Chem Biol 2005;9:366370. 20. Bembenek SD, Tounge BA, Reynolds CH. Ligand efciency and fragment-based drug discovery. Drug Discov Today 2009;14:278283. 21. Fruh V, Zhou Y, Chen D, Loch C, Ab E, Grinkova YN, Verheij H, Sligar SG, Bushweller JH, Siegal G. Application of fragment-based drug discovery to membrane proteins: Identication of ligands of the integral membrane enzyme DsbB. Chem Biol 2010;17:881891. 22. Bamborough P, Brown MJ, Christopher JA, Chung CW, Mellor GW. Selectivity of kinase inhibitor fragments. J Med Chem 2011;54:51315143. 23. Babaoglu K, Shoichet BK. Deconstructing fragment-based inhibitor discovery. Nat Chem Biol 2006;2:720723. 24. Warr WA. Fragment-based drug discovery: What really works. An interview with Sandy Farmer of Boehringer Ingelheim. J Comput Aided Mol Des 2011;25:599605. 25. Desjarlais RL. Using computational techniques in fragment-based drug discovery. Methods Enzymol 2011;493:137155. 26. Gozalbes R, Carbajo RJ, Pineda-Lucena A. Contributions of computational chemistry and biophysical techniques to fragment-based drug discovery. Curr Med Chem 2010;17:17691794. 27. Hoffer L, Renaud JP, Horvath D. Fragment-based drug design: Computational & experimental state of the art. Comb Chem High Throughput Screen 2011;14:500520. 28. Hubbard RE, Chen I, Davis B. Informatics and modeling challenges in fragment-based drug discovery. Curr Opin Drug Discov Devel 2007;10:289297. Medicinal Research Reviews DOI 10.1002/med
r 587
29. Law R, Barker O, Barker JJ, Hesterkamp T, Godemann R, Andersen O, Fryatt T, Courtney S, Hallett D, Whittaker M. The multiple roles of computational chemistry in fragment-based drug design. J Comput Aided Mol Des 2009;23:459473. 30. Vangrevelinghe E, Rudisser S. Computational approaches for fragment optimization. Curr ComputAided Drug Design 2007;3:6983. 31. Villar HO, Hansen MR. Computational techniques in fragment based drug discovery. Curr Top Med Chem 2007;7:15091513. 32. Zoete V, Grosdidier A, Michielin O. Docking, virtual high throughput screening and in silico fragment-based drug design. J Cell Mol Med 2009;13:238248. 33. Makara GM. On sampling of fragment space. J Med Chem 2007;50:32143221. 34. Delaney JS. Predicting aqueous solubility from structure. Drug Discov Today 2005;10:289295. 35. Faller B, Ertl P. Computational approaches to determine drug solubility. Adv Drug Deliv Rev 2007;59(7):533545. 36. Fejzo J, Lepre CA, Peng JW, Bemis GW, Ajay, Murcko MA, Moore JM. The SHAPES strategy: An NMR-based approach for lead generation in drug discovery. Chem Biol 1999;6:755 769. 37. Lepre C. Fragment-based drug discovery using the SHAPES method. Expert Opin Drug Discov 2007;2:15551566. 38. Chung S, Parker JB, Bianchet M, Amzel LM, Stivers JT. Impact of linker strain and exibility in the design of a fragment-based inhibitor. Nat Chem Biol 2009;5:407413. 39. Schneider G, Fechner U. Computer-based de novo design of drug-like molecules. Nat Rev Drug Discov 2005;4:649663. 40. Zhu Z, Sun ZY, Ye Y, Voigt J, Strickland C, Smith EM, Cumming J, Wang L, Wong J, Wang YS, Wyss DF, Chen X, Kuvelkar R, Kennedy ME, Favreau L, Parker E, McKittrick BA, Stamford A, Czarniecki M, Greenlee W, Hunter JC. Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part IInhibitor design and validation. J Med Chem 2010;53:951965. 41. Johnson MC, Hu Q, Lingardo L, Ferre RA, Greasley S, Yan J, Kath J, Chen P, Ermolieff J, Alton G. Novel isoquinolone PDK1 inhibitors discovered through fragment-based lead discovery. J Comput Aided Mol Des 2011;25:689698. 42. Congreve M, Carr R, Murray C, Jhoti H. A rule of three for fragment-based lead discovery? Drug Discov Today 2003;8:876877. 43. Card GL, Blasdel L, England BP, Zhang C, Suzuki Y, Gillette S, Fong D, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY. A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design. Nat Biotechnol 2005;23:201207. 44. Davies DR, Mamat B, Magnusson OT, Christensen J, Haraldsson MH, Mishra R, Pease B, Hansen E, Singh J, Zembower D, Kim H, Kiselyov AS, Burgin AB, Gurney ME, Stewart LJ. Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography. J Med Chem 2009;52:46944715. 45. Law RJ. Tetrabromobisphenol A: Investigating the worst-case scenario. Mar Pollut Bull 2009;58(4):459460. 46. Bondensgaard K, Ankersen M, Thogersen H, Hansen BS, Wulff BS, Bywater RP. Recognition of privileged structures by G-protein coupled receptors. J Med Chem 2004;47:888899. 47. Schnur DM, Hermsmeier MA, Tebben AJ. Are target-family-privileged substructures truly privileged? J Med Chem 2006;49:20002009. 48. Clark M, Wiseman JS. Fragment-based prediction of the clinical occurrence of long QT syndrome and torsade de pointes. J Chem Inf Model 2009;49:26172626. 49. PubChem database. http://www.pubchem.ncbi.nlm.nih.gov. 50. eMolecules database. http://www.emolecules.com. Medicinal Research Reviews DOI 10.1002/med
588
r SHENG AND ZHANG
51. Oprea TI, Blaney JM. Cheminformatics approaches to fragment-based lead discovery. In: Jahnke W, Erlanson DA, Eds. Fragment-Based Approaches in Drug Discovery. Methods and Principles in Medicinal Chemistry, Vol. 34. Weinheim: Wiley-VCH Verlag GmbH; 2006. pp 91111. 52. Tanaka N, Ohno K, Niimi T, Moritomo A, Mori K, Orita M. Small-world phenomena in chemical library networks: Application to fragment-based drug discovery. J Chem Inf Model 2009;49:2677 2686. 53. World Drug Index; Daylight Chemical Information Systems, Inc. PO Box 7737, Laguna Niguel, CA 92677. 54. MedChem03 database. BioByte: Claremont CA, and Daylight Chemical Information Systems, Inc.: Aliso Viejo, CA. 55. MDL Drug Data Report. Symyx Technologies, Inc.: Sunnyvale, CA. 56. Chen H, Gao J, Lu Y, Kou G, Zhang H, Fan L, Sun Z, Guo Y, Zhong Y. Preparation and characterization of PE38KDEL-loaded anti-HER2 nanoparticles for targeted cancer therapy. J Control Release 2008;128:209216. 57. Horst EVD, IJzerman AP. Computational approaches to fragment and substructure discovery and evaluation. In: Zartler ER, Shapiro MJ, Eds. Fragment-Based Drug Discovery: A Practical Approach. John Wiley & Sons, Ltd. The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom; 2008. pp 199222. 58. Zhang M, Sheng C, Xu H, Song Y, Zhang W. Constructing virtual combinatorial fragment libraries based upon MDL Drug Data Report database. Sci China Ser B 2007;50:364371. 59. Lewell XQ, Judd DB, Watson SP, Hann MM. RECAPRetrosynthetic combinatorial analysis procedure: A powerful new technique for identifying privileged molecular fragments with useful applications in combinatorial chemistry. J Chem Inf Comput Sci 1998;38:511522. 60. Bemis GW, Murcko MA. Properties of known drugs. 2. Side chains. J Med Chem 1999;42:5095 5099. 61. Bemis GW, Murcko MA. The properties of known drugs. 1. Molecular frameworks. J Med Chem 1996;39:28872893. 62. Hartenfeller M, Schneider G. De novo drug design. Methods Mol Biol 2011;672:299323. 63. Schulz MN, Landstrom J, Bright K, Hubbard RE. Design of a fragment library that maximally represents available chemical space. J Comput Aided Mol Des 2011;25:611620. 64. Rarey M, Stahl M. Similarity searching in large combinatorial chemistry spaces. J Comput Aided Mol Des 2001;15:497520. 65. Hann MM, Oprea TI. Pursuing the leadlikeness concept in pharmaceutical research. Curr Opin Chem Biol 2004;8:255263. 66. Carr RA, Congreve M, Murray CW, Rees DC. Fragment-based lead discovery: Leads by design. Drug Discov Today 2005;10:987992. 67. Mauser H, Stahl M. Chemical fragment spaces for de novo design. J Chem Inf Model 2007;47:318 324. 68. van Deursen R, Blum LC, Reymond JL. Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem. J Comput Aided Mol Des 2011;25:649662. 69. Andrews KM, Cramer RD. Toward general methods of targeted library design: Topomer shape similarity searching with diverse structures as queries. J Med Chem 2000;43:17231740. 70. Cramer RD, Soltanshahi F, Jilek R, Campbell B. AllChem: Generating and searching 10(20) synthetically accessible structures. J Comput Aided Mol Des 2007;21:341350. 71. Jilik RJ, Cramer RD. Topomers: A validated protocol for their self-consistent generation. J Chem Inf Comput Sci 2004;44:11211127. 72. Rarey M, Dixon JS. Feature trees: A new molecular similarity measure based on tree matching. J Comput Aided Mol Des 1998;12:471490. 73. Lessel U, Wellenzohn B, Lilienthal M, Claussen H. Searching fragment spaces with feature trees. J Chem Inf Model 2009;49:270279. Medicinal Research Reviews DOI 10.1002/med
r 589
74. Lee ML, Schneider G. Scaffold architecture and pharmacophoric properties of natural products and trade drugs: Application in the design of natural product-based combinatorial libraries. J Comb Chem 2001;3:284289. 75. Siegel MG, Vieth M. Drugs in other drugs: A new look at drugs as fragments. Drug Discov Today 2007;12:7179. 76. Sutherland JJ, Higgs RE, Watson I, Vieth M. Chemical fragments as foundations for understanding target space and activity prediction. J Med Chem 2008;51:26892700. 77. Grabowski K, Schneider G. Properties and architecture of drugs and natural products revisited. Curr Chem Biol 2007;1:115127. 78. Wang J, Hou T. Drug and drug candidate building block analysis. J Chem Inf Model 2010;50:5567. 79. Vieth M, Siegel M. Structural fragments in marketed oral drugs. In: Jahnke W, Erlanson DA, Eds. Fragment-Based Approaches in Drug Discovery. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA; 2006. pp 113124. 80. Morphy R, Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem 2005;48:65236543. 81. Sheridan RP. Finding multiactivity substructures by mining databases of drug-like compounds. J Chem Inf Comput Sci 2003;43:10371050. 82. Sheridan RP. The most common chemical replacements in drug-like compounds. J Chem Inf Comput Sci 2002;42:103108. 83. Ertl P. Cheminformatics analysis of organic substituents: Identication of the most common substituents, calculation of substituent properties, and automatic identication of drug-like bioisosteric groups. J Chem Inf Comput Sci 2003;43:374380. 84. Haubertin DY, Bruneau P. A database of historically-observed chemical replacements. J Chem Inf Model 2007;47:12941302. 85. Kho R, Hodges JA, Hansen MR, Villar HO. Ring systems in mutagenicity databases. J Med Chem 2005;48:66716678. 86. Kazius J, Nijssen S, Kok J, Back T, Ijzerman AP. Substructure mining using elaborate chemical representation. J Chem Inf Model 2006;46:597605. 87. Batista J, Godden JW, Bajorath J. Assessment of molecular similarity from the analysis of randomly generated structural fragment populations. J Chem Inf Model 2006;46:19371944. 88. Batista J, Bajorath J. Chemical database mining through entropy-based molecular similarity assessment of randomly generated structural fragment populations. J Chem Inf Model 2007;47:5968. 89. Batista J, Bajorath J. Mining of randomly generated molecular fragment populations uncovers activity-specic fragment hierarchies. J Chem Inf Model 2007;47:14051413. 90. Lounkine E, Auer J, Bajorath J. Formal concept analysis for the identication of molecular fragment combinations specic for active and highly potent compounds. J Med Chem 2008;51:53425348. 91. Lameijer EW, Kok JN, Back T, Ijzerman AP. Mining a chemical database for fragment cooccurrence: Discovery of chemical cliches. J Chem Inf Model 2006;46:553562. 92. Wilkens SJ, Janes J, Su AI. HierS: Hierarchical scaffold clustering using topological chemical graphs. J Med Chem 2005;48:31823193. 93. Schuffenhauer A, Ertl P, Roggo S, Wetzel S, Koch MA, Waldmann H. The scaffold tree Visualization of the scaffold universe by hierarchical scaffold classication. J Chem Inf Model 2007;47:4758. 94. Shelat AA, Guy RK. Scaffold composition and biological relevance of screening libraries. Nat Chem Biol 2007;3:442446. 95. Clark AM, Labute P. Detection and assignment of common scaffolds in project databases of lead molecules. J Med Chem 2009;52:469483. 96. Clark AM. 2D depiction of fragment hierarchies. J Chem Inf Model 2010;50:3746. 97. Agraotis DK, Wiener JJ. Scaffold explorer: An interactive tool for organizing and mining structureactivity data spanning multiple chemotypes. J Med Chem 2010;53:50025011. Medicinal Research Reviews DOI 10.1002/med
590
r SHENG AND ZHANG
98. Renner S, van Otterlo WA, Dominguez Seoane M, Mocklinghoff S, Hofmann B, Wetzel S, Schuffenhauer A, Ertl P, Oprea TI, Steinhilber D, Brunsveld L, Rauh D, Waldmann H. Bioactivity-guided mapping and navigation of chemical space. Nat Chem Biol 2009;5:585592. 99. Wetzel S, Klein K, Renner S, Rauh D, Oprea TI, Mutzel P, Waldmann H. Interactive exploration of chemical space with Scaffold Hunter. Nat Chem Biol 2009;5:581583. 100. Hopkins AL, Groom CR, Alex A. Ligand efciency: A useful metric for lead selection. Drug Discov Today 2004;9:430431. 101. Mocklinghoff S, van Otterlo WA, Rose R, Fuchs S, Zimmermann TJ, Dominguez Seoane M, Waldmann H, Ottmann C, Brunsveld L. Design and evaluation of fragment-like estrogen receptor tetrahydroisoquinoline ligands from a scaffold-detection approach. J Med Chem 2011;54:2005 2011. 102. Mattos C, Bellamacina CR, Peisach E, Pereira A, Vitkup D, Petsko GA, Ringe D. Multiple solvent crystal structures: Probing binding sites, plasticity and hydration. J Mol Biol 2006;357:1471 1482. 103. Mattos C, Ringe D. Locating and characterizing binding sites on proteins. Nat Biotechnol 1996;14:595599. 104. Leis S, Schneider S, Zacharias M. In silico prediction of binding sites on proteins. Curr Med Chem 2010;17:15501562. 105. Laurie AT, Jackson RM. Methods for the prediction of protein-ligand binding sites for structurebased drug design and virtual ligand screening. Curr Protein Pept Sci 2006;7:395406. 106. Goodford PJ. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 1985;28:849857. 107. von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Van Phan T, Smythe ML, White HF, Oliver SW, Colman PM, Varghese JN, Ryan DM, Woods JM, Bethell RC, Hotham VJ, Cameron JM, Penn CR. Rational design of potent sialidase-based inhibitors of inuenza virus replication. Nature 1993;363:418423. 108. Miranker A, Karplus M. Functionality maps of binding sites: A multiple copy simultaneous search method. Proteins 1991;11:2934. 109. Schubert C, Stultz C. The multi-copy simultaneous search methodology: A fundamental tool for structure-based drug design. J Comput Aided Mol Des 2009;23:475489. 110. Campbell SJ, Gold ND, Jackson RM, Westhead DR. Ligand binding: Functional site location, similarity and docking. Curr Opin Struct Biol 2003;13:389395. 111. Sotriffer C, Klebe G. Identication and mapping of small-molecule binding sites in proteins: Computational tools for structure-based drug design. Farmaco 2002;57:243251. 112. Landon M, Lieberman R, Hoang Q, Ju S, Caaveiro J, Orwig S, Kozakov D, Brenke R, Chuang G, Beglov D, Vajda S, Petsko G, Ringe D. Detection of ligand binding hot spots on protein surfaces via fragment-based methods: Application to DJ-1 and glucocerebrosidase. J Comput Aided Mol Des 2009;23:491500. 113. Clark M, Guarnieri F, Shkurko I, Wiseman J. Grand canonical Monte Carlo simulation of ligandprotein binding. J Chem Inf Model 2006;46:231242. 114. Irwin JJ, Shoichet BK. ZINCA free database of commercially available compounds for virtual screening. J Chem Inf Model 2005;45:177182. 115. Nayal M, Honig B. On the nature of cavities on protein surfaces: Application to the identication of drug-binding sites. Proteins 2006;63:892906. 116. Leach AR, Shoichet BK, Peishoff CE. Prediction of protein-ligand interactions. Docking and scoring: Successes and gaps. J Med Chem 2006;49:58515855. 117. Teotico DG, Babaoglu K, Rocklin GJ, Ferreira RS, Giannetti AM, Shoichet BK. Docking for fragment inhibitors of AmpC beta-lactamase. Proc Natl Acad Sci USA 2009;106:74557460. 118. Ferrara P, Gohlke H, Price DJ, Klebe G, Brooks CL, 3rd. Assessing scoring functions for proteinligand interactions. J Med Chem 2004;47:30323047. Medicinal Research Reviews DOI 10.1002/med
r 591
119. Majeux N, Scarsi M, Caisch A. Efcient electrostatic solvation model for protein-fragment docking. Proteins 2001;42:256268. 120. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 2004;47:1739 1749. 121. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 2004;47:17501759. 122. Kawatkar S, Wang H, Czerminski R, Joseph-McCarthy D. Virtual fragment screening: An exploration of various docking and scoring protocols for fragments using Glide. J Comput Aided Mol Des 2009 23:527539. 123. Sandor M, Kiss R, Keseru GM. Virtual fragment docking by Glide: A validation study on 190 protein-fragment complexes. J Chem Inf Model 2010;50:11651172. 124. Verdonk ML, Giangreco I, Hall RJ, Korb O, Mortenson PN, Murray CW. Docking performance of fragments and druglike compounds. J Med Chem 2011;54:54225431. 125. Knehans T, Schuller A, Doan DN, Nacro K, Hill J, Guntert P, Madhusudhan MS, Weil T, Vasudevan SG. Structure-guided fragment-based in silico drug design of dengue protease inhibitors. J Comput Aided Mol Des 2011;25:263274. 126. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: Automated docking with selective receptor exibility. J Comput Chem 2009;30:27852791. 127. Al-qattan MN, Mordi MN. Site-directed fragment-based generation of virtual sialic acid databases against inuenza A hemagglutinin. J Mol Model 2010;16:975991. 128. Vadivelan S, Sinha BN, Tajne S, Jagarlapudi SA. Fragment and knowledge-based design of selective GSK-3beta inhibitors using virtual screening models. Eur J Med Chem 2009;44:23612371. 129. Brough PA, Barril X, Borgognoni J, Chene P, Davies NG, Davis B, Drysdale MJ, Dymock B, Eccles SA, Garcia-Echeverria C, Fromont C, Hayes A, Hubbard RE, Jordan AM, Jensen MR, Massey A, Merrett A, Padeld A, Parsons R, Radimerski T, Raynaud FI, Robertson A, Roughley SD, Schoepfer J, Simmonite H, Sharp SY, Surgenor A, Valenti M, Walls S, Webb P, Wood M, Workman P, Wright L. Combining hit identication strategies: Fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem 2009;52:47944809. 130. Gleeson MP, Gleeson D. QM/MM as a tool in fragment based drug discovery. A cross-docking, rescoring study of kinase inhibitors. J Chem Inf Model 2009;49:14371448. 131. Marcou G, Rognan D. Optimizing fragment and scaffold docking by use of molecular interaction ngerprints. J Chem Inf Model 2007;47:195207. 132. Fukunishi Y, Mashimo T, Orita M, Ohno K, Nakamura H. In silico fragment screening by replica generation (FSRG) method for fragment-based drug design. J Chem Inf Model 2009;49:925933. 133. Li H, Li C. Multiple ligand simultaneous docking: Orchestrated dancing of ligands in binding sites of protein. J Comput Chem 2010;31:20142022. 134. Li H, Liu A, Zhao Z, Xu Y, Lin J, Jou D, Li C. Fragment-based drug design and drug repositioning using multiple ligand simultaneous docking (MLSD): Identifying celecoxib and template compounds as novel inhibitors of signal transducer and activator of transcription 3 (STAT3). J Med Chem 2011;54:55925596. 135. Ekonomiuk D, Su XC, Ozawa K, Bodenreider C, Lim SP, Otting G, Huang D, Caisch A. Flaviviral protease inhibitors identied by fragment-based library docking into a structure generated by molecular dynamics. J Med Chem 2009;52:48604868. 136. Danziger DJ, Dean PM. Automated site-directed drug design: A general algorithm for knowledge acquisition about hydrogen-bonding regions at protein surfaces. Proc R Soc Lond B Biol Sci 1989;236:101113. Medicinal Research Reviews DOI 10.1002/med
592
r SHENG AND ZHANG
137. Clark DE, Westhead DR. Evolutionary algorithms in computer-aided molecular design. J Comput Aided Mol Des 1996;10:337358. 138. Dorigo M, Di Caro G, Gambardella LM. Ant algorithms for discrete optimization. Artif Life 1999;5:137172. 139. Hiss JA, Hartenfeller M, Schneider G. Concepts and applications of natural computing techniques in de novo drug and peptide design. Curr Pharm Des 2010;16:16561665. 140. DeWitt R, Shaknovich E. SmoG: De novo design method based on simple, fast, and accurate free energy estimates. 1. Methodology and supporting evidence. J Am Chem Soc 1996;118:1173311744. 141. DeWitt R, Shaknovich E. SmoG: De novo design method based on simple, fast, and accurate free energy estimates. 2. Case studies on molecular design. J Am Chem Soc 1997;119:46084617. 142. Bohacek RS, McMartin C. Multiple highly diverse structures complementary to enzyme binding sites: Results of extensive application of de novo design method incorporating combinatorial growth. J Am Chem Soc 1994;116:55605571. 143. Rotstein SH, Murcko MA. GroupBuild: A fragment-based method for de novo drug design. J Med Chem 1993;36:17001710. 144. Gillet VJ, Newell W, Mata P, Myatt G, Sike S, Zsoldos Z, Johnson AP. SPROUT: Recent developments in the de novo design of molecules. J Chem Inf Comput Sci 1994;34:207217. 145. Moon JB, Howe WJ. Computer design of bioactive molecules: A method for receptor-based de novo ligand design. Proteins 1991;11:314328. 146. Rarey M, Kramer B, Lengauer T, Klebe G. A fast exible docking method using an incremental construction algorithm. J Mol Biol 1996;261:470489. 147. Degen J, Rarey M. FlexNovo: Structure-based searching in large fragment spaces. ChemMedChem 2006;1:854868. 148. Zaliani A, Boda K, Seidel T, Herwig A, Schwab CH, Gasteiger J, Clauen H, Lemmen C, Degen J, P arn J, Rarey M. Second-generation de novo design: A view from a medicinal chemist perspective. J Comput Aided Mol Des 2009;23:593602. 149. Boehm M, Wu TY, Claussen H, Lemmen C. Similarity searching and scaffold hopping in synthetically accessible combinatorial chemistry spaces. J Med Chem 2008;51:24682480. 150. Parn J, Degen J, Rarey M. Exploring fragment spaces under multiple physicochemical constraints. J Comput Aided Mol Des 2007;21:327340. 151. Durrant JD, Amaro RE, McCammon JA. AutoGrow: A novel algorithm for protein inhibitor design. Chem Biol Drug Des 2009;73:168178. 152. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998;19:16391662. 153. Kutchukian PS, Lou D, Shakhnovich EI. FOG: Fragment Optimized Growth algorithm for the de novo generation of molecules occupying druglike chemical space. J Chem Inf Model 2009;49:1630 1642. 154. Pearlman DA, Murcko MA. CONCERTS: Dynamic connection of fragments as an approach to de novo ligand design. J Med Chem 1996;39:16511663. 155. Bohm HJ. The computer program LUDI: A new method for the de novo design of enzyme inhibitors. J Comput Aided Mol Des 1992;6:6178. 156. Bohm HJ. On the use of LUDI to search the Fine Chemicals Directory for ligands of proteins of known three-dimensional structure. J Comput Aided Mol Des 1994;8:623632. 157. Lauri G, Bartlett PA. CAVEAT: A program to facilitate the design of organic molecules. J Comput Aided Mol Des 1994;8:5166. 158. Tschinke V, Cohen NC. The NEWLEAD program: A new method for the design of candidate structures from pharmacophoric hypotheses. J Med Chem 1993;36:38633870. 159. Miranker A, Karplus M. An automated method for dynamic ligand design. Proteins 1995;23:472 490. Medicinal Research Reviews DOI 10.1002/med
r 593
160. Roe DC, Kuntz ID. BUILDER v.2: Improving the chemistry of a de novo design strategy. J Comput Aided Mol Des 1995;9:269282. 161. Stahl M, Todorov NP, James T, Mauser H, Boehm HJ, Dean PM. A validation study on the practical use of automated de novo design. J Comput Aided Mol Des 2002;16:459478. 162. Dey F, Caisch A. Fragment-based de novo ligand design by multiobjective evolutionary optimization. J Chem Inf Model 2008;48:679690. 163. Majeux N, Scarsi M, Apostolakis J, Ehrhardt C, Caisch A. Exhaustive docking of molecular fragments with electrostatic solvation. Proteins 1999;37:88105. 164. Ji H, Stanton BZ, Igarashi J, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB. Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors. J Am Chem Soc 2008;130:39003914. 165. Ji H, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB. Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping. J Med Chem 2009;52:779 797. 166. Yuan Y, Pei J, Lai L. LigBuilder 2: A practical de novo drug design approach. J Chem Inf Model 2011;51:10831091. 167. Wang R, Gao Y, Lai L. A multi-purpose program for structure-based drug design. J Mol Model 2000;6:498516. 168. Boda K, Seidel T, Gasteiger J. Structure and reaction based evaluation of synthetic accessibility. J Comput Aided Mol Des 2007;21:311325. 169. Meunier B. Hybrid molecules with a dual mode of action: Dream or reality? Acc Chem Res 2008;41:6977. 170. Viegas-Junior C, Danuello A, da Silva Bolzani V, Barreiro EJ, Fraga CA. Molecular hybridization: A useful tool in the design of new drug prototypes. Curr Med Chem 2007;14:18291852. 171. Pierce AC, Rao G, Bemis GW. BREED: Generating novel inhibitors through hybridization of known ligands. Application to CDK2, p38, and HIV protease. J Med Chem 2004;47:27682775. 172. Li Y, Zhao Y, Liu Z, Wang R. Automatic tailoring and transplanting: A practical method that makes virtual screening more useful. J Chem Inf Model 2011;51:14741491. 173. Nisius B, Rester U. Fragment shufing: An automated workow for three-dimensional fragmentbased ligand design. J Chem Inf Model 2009;49:12111222. 174. Moriaud F, Doppelt-Azeroual O, Martin L, Oguievetskaia K, Koch K, Vorotyntsev A, Adcock SA, Delfaud F. Computational fragment-based approach at PDB scale by protein local similarity. J Chem Inf Model 2009;49:280294. 175. Doppelt O, Moriaud F, Bornot A, de Brevern AG. Functional annotation strategy for protein structures. Bioinformation 2007;1:357359. 176. Jambon M, Andrieu O, Combet C, Deleage G, Delfaud F, Geourjon C. The SuMo server: 3D search for protein functional sites. Bioinformatics 2005;21:39293930. 177. Schneider G, Neidhart W, Giller T, Schmid G. Scaffold-Hopping by topological pharmacophore search: A contribution to virtual screening. Angew Chem Int Ed Engl 1999;38:28942896. 178. Krueger BA, Dietrich A, Baringhaus KH, Schneider G. Scaffold-hopping potential of fragmentbased de novo design: The chances and limits of variation. Comb Chem High Throughput Screen 2009;12:383396. 179. Maass P, Schulz-Gasch T, Stahl M, Rarey M. Recore: A fast and versatile method for scaffold hopping based on small molecule crystal structure conformations. J Chem Inf Model 2007;47:390 399. 180. Schneider G, Hartenfeller M, Reutlinger M, Tanrikulu Y, Proschak E, Schneider P. Voyages to the (un)known: Adaptive design of bioactive compounds. Trends Biotechnol 2009;27:1826. 181. Hartenfeller M, Proschak E, Schuller A, Schneider G. Concept of combinatorial de novo design of drug-like molecules by particle swarm optimization. Chem Biol Drug Des 2008;72:1626. Medicinal Research Reviews DOI 10.1002/med
594
r SHENG AND ZHANG
182. Fechner U, Schneider G. Flux (1): A virtual synthesis scheme for fragment-based de novo design. J Chem Inf Model 2006;46:699707. 183. Fechner U, Schneider G. Flux (2): Comparison of molecular mutation and crossover operators for ligand-based de novo design. J Chem Inf Model 2007;47:656667. 184. Proschak E, Zettl H, Tanrikulu Y, Weisel M, Kriegl JM, Rau O, Schubert-Zsilavecz M, Schneider G. From molecular shape to potent bioactive agents I: Bioisosteric replacement of molecular fragments. ChemMedChem 2009;4:4144. 185. Proschak E, Sander K, Zettl H, Tanrikulu Y, Rau O, Schneider P, Schubert-Zsilavecz M, Stark H, Schneider G. From molecular shape to potent bioactive agents II: Fragment-based de novo design. ChemMedChem 2009;4:4548. 186. EA-InVentor; Tripos International: St. Louis, MO. http://www.tripos.com. 187. Damewood JR, Jr, Lerman CL, Masek BB. NovoFLAP: A ligand-based de novo design approach for the generation of medicinally relevant ideas. J Chem Inf Model 2010;50:12961303. 188. Feher M, Gao Y, Baber JC, Shirley WA, Saunders J. The use of ligand-based de novo design for scaffold hopping and sidechain optimization: Two case studies. Bioorg Med Chem 2008;16:422427. 189. Liu Q, Masek B, Smith K, Smith J. Tagged fragment method for evolutionary structure-based de novo lead generation and optimization. J Med Chem 2007;50:53925402. 190. Masek BB, Shen L, Smith KM, Pearlman RS. Sharing chemical information without sharing chemical structure. J Chem Inf Model 2008;48:256261. 191. Pham TA, Jain AN. Parameter estimation for scoring protein-ligand interactions using negative training data. J Med Chem 2006;49:58565868. 192. Jain AN. Surex: Fully automatic exible molecular docking using a molecular similarity-based search engine. J Med Chem 2003;46:499511. 193. Huang Q, Li LL, Yang SY. PhDD: A new pharmacophore-based de novo design method of drug-like molecules combined with assessment of synthetic accessibility. J Mol Graph Model 2010;28:775 787. 194. Vieth M, Erickson J, Wang J, Webster Y, Mader M, Higgs R, Watson I. Kinase inhibitor data modeling and de novo inhibitor design with fragment approaches. J Med Chem 2009;52:64566466. 195. Liew CY, Ma XH, Liu X, Yap CW. SVM model for virtual screening of Lck inhibitors. J Chem Inf Model 2009;49:877885. 196. Loving K, Alberts I, Sherman W. Computational approaches for fragment-based and de novo design. Curr Top Med Chem 2010;10:1432. 197. Massova I, Kollman PA. Computational alanine scanning to probe protein-protein interactions: A novel approach to evaluate binding free energies. J Am Chem Soc 1999;121:81338143. 198. Still WC, Tempczyk A, Hawley RC, Hendrickson T. Semianalytical treatment of solvation for molecular mechanics and dynamics. J Am Chem Soc 1990;112:61276129. 199. Kim JT, Hamilton AD, Bailey CM, Domaoal RA, Wang L, Anderson KS, Jorgensen WL. FEPguided selection of bicyclic heterocycles in lead optimization for non-nucleoside inhibitors of HIV-1 reverse transcriptase. J Am Chem Soc 2006;128:1537215373. 200. Kollman PA. Free energy calculations: Applications to chemical and biochemical phenomena. Chem Rev 1993;93:23952417. 201. Oostenbrink C, van Gunsteren WF. Free energies of binding of polychlorinated biphenyls to the estrogen receptor from a single simulation. Proteins 2004;54:237246. 202. van Gunsteren WF, Berendsen HJ. Thermodynamic cycle integration by computer simulation as a tool for obtaining free energy differences in molecular chemistry. J Comput Aided Mol Des 1987;1:171176. 203. Fogel GB. Computational intelligence approaches for pattern discovery in biological systems. Brief Bioinform 2008;9:307316. 204. Hecht D, Fogel GB. A novel in silico approach to drug discovery via computational intelligence. J Chem Inf Model 2009;49:11051121. Medicinal Research Reviews DOI 10.1002/med
r 595
205. Nicolaou CA, Apostolakis J, Pattichis CS. De novo drug design using multiobjective evolutionary graphs. J Chem Inf Model 2009;49:295307. 206. Schneider G, Lee ML, Stahl M, Schneider P. De novo design of molecular architectures by evolutionary assembly of drug-derived building blocks. J Comput Aided Mol Des 2000;14:487 494. 207. Vinkers HM, de Jonge MR, Daeyaert FF, Heeres J, Koymans LM, van Lenthe JH, Lewi PJ, Timmerman H, Van Aken K, Janssen PA. SYNOPSIS: SYNthesize and OPtimize System in Silico. J Med Chem 2003;46:27652773. 208. Symyx Technology Inc., 2440 Camino Ramon, Suite 300, San Ramon, CA 94583, USA. 209. Law J, Zsoldos Z, Simon A, Reid D, Liu Y, Khew SY, Johnson AP, Major S, Wade RA, Ando HY. Route Designer: A retrosynthetic analysis tool utilizing automated retrosynthetic rule generation. J Chem Inf Model 2009;49:593602. 210. Patel H, Bodkin MJ, Chen B, Gillet VJ. Knowledge-based approach to de novo design using reaction vectors. J Chem Inf Model 2009;49:11631184. 211. Reisen FH, Schneider G, Proschak E. Reaction-MQL: Line notation for functional transformation. J Chem Inf Model 2009;49:612. 212. Hartenfeller M. Development of a Computational Method for Reaction-Driven De Novo Design of Druglike Compounds. Frankfurt am Main: Goethe University; 2010. p 120. 213. Kutchukian PS, Shakhnovich EI. De novo design: Balancing novelty and conned chemical space. Expert Opin Drug Discov 2010;5:789812. 214. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001;46:326. 215. Hutter MC. In silico prediction of drug properties. Curr Med Chem 2009;16:189202. 216. Agarwal AK, Johnson AP, Fishwick CWG. Synthesis of de novo designed small-molecule inhibitors of bacterial RNA polymerase. Tetrahedron 2008;64:1004910054. 217. Alig L, Alsenz J, Andjelkovic M, Bendels S, Benardeau A, Bleicher K, Bourson A, David-Pierson P, Guba W, Hildbrand S, Kube D, Lubbers T, Mayweg AV, Narquizian R, Neidhart W, Nettekoven M, Plancher JM, Rocha C, Rogers-Evans M, Rover S, Schneider G, Taylor S, Waldmeier P. Benzodioxoles: Novel cannabinoid-1 receptor inverse agonists for the treatment of obesity. J Med Chem 2008;51:21152127. 218. Bhurruth-Alcor Y, Rost T, Jorgensen MR, Kontogiorgis C, Skorve J, Cooper RG, Sheridan JM, Hamilton WD, Heal JR, Berge RK, Miller AD. Synthesis of novel PPARalpha/gamma dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program PROTOBUILD. Org Biomol Chem 2011;9:11691188. 219. Cogan DA, Aungst R, Breinlinger EC, Fadra T, Goldberg DR, Hao MH, Kroe R, Moss N, Pargellis C, Qian KC, Swinamer AD. Structure-based design and subsequent optimization of 2tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase. Bioorg Med Chem Lett 2008;18:32513255. 220. Cumming J, Babu S, Huang Y, Carrol C, Chen X, Favreau L, Greenlee W, Guo T, Kennedy M, Kuvelkar R, Le T, Li G, McHugh N, Orth P, Ozgur L, Parker E, Saionz K, Stamford A, Strickland C, Tadesse D, Voigt J, Zhang L, Zhang Q. Piperazine sulfonamide BACE1 inhibitors: Design, synthesis, and in vivo characterization. Bioorg Med Chem Lett 2010;20:28372842. 221. Cumming JN, Le TX, Babu S, Carroll C, Chen X, Favreau L, Gaspari P, Guo T, Hobbs DW, Huang Y, Iserloh U, Kennedy ME, Kuvelkar R, Li G, Lowrie J, McHugh NA, Ozgur L, Pan J, Parker EM, Saionz K, Stamford AW, Strickland C, Tadesse D, Voigt J, Wang L, Wu Y, Zhang L, Zhang Q. Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors. Bioorg Med Chem Lett 2008;18:32363241. 222. Dong X, Zhang Z, Wen R, Shen J, Shen X, Jiang H. Structure-based de novo design, synthesis, and biological evaluation of the indole-based PPARgamma ligands (I). Bioorg Med Chem Lett 2006;16:59135916. Medicinal Research Reviews DOI 10.1002/med
596
r SHENG AND ZHANG
223. Firth-Clark S, Willems HM, Williams A, Harris W. Generation and selection of novel estrogen receptor ligands using the de novo structure-based design tool, SkelGen. J Chem Inf Model 2006;46:642 647. 224. Hangeland JJ, Cheney DL, Friends TJ, Swartz S, Levesque PC, Rich AJ, Sun L, Bridal TR, Adam LP, Normandin DE, Murugesan N, Ewing WR. Design and SAR of selective T-type calcium channel antagonists containing a biaryl sulfonamide core. Bioorg Med Chem Lett 2008;18:474478. 225. Heikkila T, Thirumalairajan S, Davies M, Parsons MR, McConkey AG, Fishwick CW, Johnson AP. The rst de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg Med Chem Lett 2006;16:8892. 226. Herschhorn A, Lerman L, Weitman M, Gleenberg IO, Nudelman A, Hizi A. De novo parallel design, synthesis and evaluation of inhibitors against the reverse transcriptase of human immunodeciency virus type-1 and drug-resistant variants. J Med Chem 2007;50:23702384. 227. Kandil S, Biondaro S, Vlachakis D, Cummins AC, Coluccia A, Berry C, Leyssen P, Neyts J, Brancale A. Discovery of a novel HCV helicase inhibitor by a de novo drug design approach. Bioorg Med Chem Lett 2009;19:29352937. 228. Liu B, Joseph RW, Dorsey BD, Schiksnis RA, Northrop K, Bukhtiyarova M, Springman EB. Structure-based design of substituted biphenyl ethylene ethers as ligands binding in the hydrophobic pocket of gp41 and blocking the helical bundle formation. Bioorg Med Chem Lett 2009;19:5693 5697. 229. Moore WR, Jr. Maximizing discovery efciency with a computationally driven fragment approach. Curr Opin Drug Discov Devel 2005;8:355364. 230. Park H, Bahn YJ, Ryu SE. Structure-based de novo design and biochemical evaluation of novel Cdc25 phosphatase inhibitors. Bioorg Med Chem Lett 2009;19:43304334. 231. Schuller A, Suhartono M, Fechner U, Tanrikulu Y, Breitung S, Scheffer U, Gobel MW, Schneider G. The concept of template-based de novo design from drug-derived molecular fragments and its application to TAR RNA. J Comput Aided Mol Des 2008;22:5968. 232. Sova M, Cadez G, Turk S, Majce V, Polanc S, Batson S, Lloyd AJ, Roper DI, Fishwick CW, Gobec S. Design and synthesis of new hydroxyethylamines as inhibitors of D-alanyl-D-lactate ligase (VanA) and D-alanyl-D-alanine ligase (DdlB). Bioorg Med Chem Lett 2009;19:13761379. 233. Zhao L, Huang W, Liu H, Wang L, Zhong W, Xiao J, Hu Y, Li S. FK506-binding protein ligands: Structure-based design, synthesis, and neurotrophic/neuroprotective properties of substituted 5,5dimethyl-2-(4-thiazolidine)carboxylates. J Med Chem 2006;49:40594071. 234. Silverman RB. Design of selective neuronal nitric oxide synthase inhibitors for the prevention and treatment of neurodegenerative diseases. Acc Chem Res 2009;42:439451. 235. Crane BR, Arvai AS, Ghosh DK, Wu C, Getzoff ED, Stuehr DJ, Tainer JA. Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science 1998;279:21212126. 236. Raman CS, Li H, Martasek P, Kral V, Masters BS, Poulos TL. Crystal structure of constitutive endothelial nitric oxide synthase: A paradigm for pterin function involving a novel metal center. Cell 1998;95:939950. 237. Fischmann TO, Hruza A, Niu XD, Fossetta JD, Lunn CA, Dolphin E, Prongay AJ, Reichert P, Lundell DJ, Narula SK, Weber PC. Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation. Nat Struct Biol 1999;6:233242. 238. Li H, Shimizu H, Flinspach M, Jamal J, Yang W, Xian M, Cai T, Wen EZ, Jia Q, Wang PG, Poulos TL. The novel binding mode of N-alkyl-N-hydroxyguanidine to neuronal nitric oxide synthase provides mechanistic insights into NO biosynthesis. Biochemistry 2002;41:1386813875. 239. Ji H, Delker SL, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB. Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives. J Med Chem 2010;53:78047824. 240. Ji H, Tan S, Igarashi J, Li H, Derrick M, Martasek P, Roman LJ, Vasquez-Vivar J, Poulos TL, Silverman RB. Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Ann Neurol 2009;65:209217. Medicinal Research Reviews DOI 10.1002/med
r 597
241. Fischer G, Gallay P, Hopkins S. Cyclophilin inhibitors for the treatment of HCV infection. Curr Opin Investig Drugs 2010;11:911918. 242. Obchoei S, Wongkhan S, Wongkham C, Li M, Yao Q, Chen C. Cyclophilin A: Potential functions and therapeutic target for human cancer. Med Sci Monit 2009;15:221232. 243. Satoh K, Shimokawa H, Berk BC. Cyclophilin A: Promising new target in cardiovascular therapy. Circ J 2010;74:22492256. 244. Guichou JF, Viaud J, Mettling C, Subra G, Lin YL, Chavanieu A. Structure-based design, synthesis, and biological evaluation of novel inhibitors of human cyclophilin A. J Med Chem 2006;49:900910. 245. Ni S, Yuan Y, Huang J, Mao X, Lv M, Zhu J, Shen X, Pei J, Lai L, Jiang H, Li J. Discovering potent small molecule inhibitors of cyclophilin A using de novo drug design approach. J Med Chem 2009;52:52955298. 246. Nugiel DA, Krumrine JR, Hill DC, Damewood JR, Jr, Bernstein PR, Sobotka-Briner CD, Liu J, Zacco A, Pierson ME. De novo design of a picomolar nonbasic 5-HT(1B) receptor antagonist. J Med Chem 2010;53:18761880. 247. Ji H, Zhang W, Zhou Y, Zhang M, Zhu J, Song Y, Lu J. A three-dimensional model of lanosterol 14alpha-demethylase of Candida albicans and its interaction with azole antifungals. J Med Chem 2000;43:24932505. 248. Sheng C, Miao Z, Ji H, Yao J, Wang W, Che X, Dong G, Lu J, Guo W, Zhang W. Threedimensional model of lanosterol 14 alpha-demethylase from Cryptococcus neoformans: Active-site characterization and insights into azole binding. Antimicrob Agents Chemother 2009;53:34873495. 249. Sheng C, Zhang W, Zhang M, Song Y, Ji H, Zhu J, Yao J, Yu J, Yang S, Zhou Y, Lu J. Homology modeling of lanosterol 14alpha-demethylase of Candida albicans and Aspergillus fumigatus and insights into the enzyme-substrate interactions. J Biomol Struct Dyn 2004;22:9199. 250. Sheng C, Zhang W. New lead structures in antifungal drug discovery. Curr Med Chem 2011;18:733 766. 251. Sheng C, Zhang W, Ji H, Zhang M, Song Y, Xu H, Zhu J, Miao Z, Jiang Q, Yao J, Zhou Y, Lu J. Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking. J Med Chem 2006;49:25122525. 252. Che X, Sheng C, Wang W, Cao Y, Xu Y, Ji H, Dong G, Miao Z, Yao J, Zhang W. New azoles with potent antifungal activity: Design, synthesis and molecular docking. Eur J Med Chem 2009;44(10):42184226. 253. Sheng C, Che X, Wang W, Wang S, Cao Y, Yao J, Miao Z, Zhang W. Structure-based design, synthesis, and antifungal activity of new triazole derivatives. Chem Biol Drug Des 2011;78:309313. 254. Sheng C, Wang W, Che X, Dong G, Wang S, Ji H, Miao Z, Yao J, Zhang W. Improved model of lanosterol 14alpha-demethylase by ligand-supported homology modeling: Validation by virtual screening and azole optimization. ChemMedChem 2010;5:390397. 255. Wang W, Sheng C, Che X, Ji H, Cao Y, Miao Z, Yao J, Zhang W. Discovery of highly potent novel antifungal azoles by structure-based rational design. Bioorg Med Chem Lett 2009;19:59655969. 256. Wang W, Sheng C, Che X, Ji H, Miao Z, Yao J, Zhang WN. Design, synthesis, and antifungal activity of novel conformationally restricted triazole derivatives. Arch Pharm (Weinheim) 2009;342:732 739. 257. Wang W, Wang S, Liu Y, Dong G, Cao Y, Miao Z, Yao J, Zhang W, Sheng C. Novel conformationally restricted triazole derivatives with potent antifungal activity. Eur J Med Chem 2010;45:6020 6026. 258. Xu Y, Sheng C, Wang W, Che X, Cao Y, Dong G, Wang S, Ji H, Miao Z, Yao J, Zhang W. Structurebased rational design, synthesis and antifungal activity of oxime-containing azole derivatives. Bioorg Med Chem Lett 2010;20:29422945. 259. Gao S, Tao X, Sun L, Sheng C, Zhang W, Yun Y, Li J, Miao H, Chen W. An liquid chromatographytandem mass spectrometry assay for determination of trace amount of new antifungal drug iodiconazole in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2009;877:382 386. Medicinal Research Reviews DOI 10.1002/med
598
r SHENG AND ZHANG
260. Sun N, Wen J, Lu G, Hong Z, Fan G, Wu Y, Sheng C, Zhang W. An ultra-fast LC method for the determination of iodiconazole in microdialysis samples and its application in the calibration of laboratory-made linear probes. J Pharm Biomed Anal 2010;51:248251. 261. Wen J, Fan GR, Hong ZY, Chai YF, Yin XP, Wu YT, Sheng CQ, Zhang WN. High performance liquid chromatographic determination of a new antifungal compound, ADKZ in rat plasma. J Pharm Biomed Anal 2007;43:655658. 262. Ji H, Zhang W, Zhang M, Kudo M, Aoyama Y, Yoshida Y, Sheng C, Song Y, Yang S, Zhou Y, Lu J, Zhu J. Structure-based de novo design, synthesis, and biological evaluation of non-azole inhibitors specic for lanosterol 14alpha-demethylase of fungi. J Med Chem 2003;46:474485. 263. Sheng C, Che X, Wang W, Wang S, Cao Y, Yao J, Miao Z, Zhang W. Design and synthesis of antifungal benzoheterocyclic derivatives by scaffold hopping. Eur J Med Chem 2011;46:17061712. 264. Tang H, Zheng C, Lv J, Wu J, Li Y, Yang H, Fu B, Li C, Zhou Y, Zhu J. Synthesis and antifungal activities in vitro of novel pyrazino [2,1-a] isoquinolin derivatives. Bioorg Med Chem Lett 2010;20:979982. 265. Tang H, Zheng CH, Zhu J, Fu BY, Zhou YJ, Lv JG. Design and synthesis of novel pyrazino[2,1a]isoquinolin derivatives with potent antifungal activity. Arch Pharm (Weinheim) 2010;343:360366. 266. Yao B, Ji H, Cao Y, Zhou Y, Zhu J, Lu J, Li Y, Chen J, Zheng C, Jiang Y, Liang R, Tang H. Synthesis and antifungal activities of novel 2-aminotetralin derivatives. J Med Chem 2007;50:52935300. 267. Roche O, Rodriguez Sarmiento RM. A new class of histamine H3 receptor antagonists derived from ligand based design. Bioorg Med Chem Lett 2007;17:36703675.
Chunquan Sheng received his bachelor degree in pharmacy (2000) and PhD degree in medicinal chemistry (2005) from Second Military Medical University. Dr. Sheng was appointed to the faculty at the Department of Medicinal Chemistry, School of Pharmacy in 2005, where he is presently an Associate Professor of Medicinal Chemistry and the Deputy Director of Department of Medicinal Chemistry. His research interests are mainly in computer-aided drug design and synthetic medicinal chemistry. Wannian Zhang received his bachelor degree in pharmacy (1968) and MS degree in medicinal chemistry (1981) from Second Military Medical University. He worked as a Professor of Medicinal Chemistry and the Director of Department of Medicinal Chemistry, School of Pharmacy Second Military Medical University in 1992. From 1994 to 2001, Prof. Zhang was appointed as the Dean of School of Pharmacy. Now, Prof. Zhang is the Chief of The States Key Discipline of Medicinal Chemistry, Second Military Medical University. His research interests are mainly in antifungal and antitumor drug design and development.

Med 21255

Încărcat de

Informații document

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Med 21255

Încărcat de

Drepturi de autor:

Formate disponibile

Fragment Informatics and Computational Fragment-Based Drug Design: An Overview and Update

Chunquan Sheng and Wannian Zhang

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD 1. INTRODUCTION

The complementarity between computational and experimental FBDD.

Medicinal Research Reviews DOI 10.1002/med

r SHENG AND ZHANG

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG

The inuence of fragment informatics to FBDD.

Medicinal Research Reviews DOI 10.1002/med

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG

3D-RISMbased method Grand canonical Monte Carlo simulation Barrils method

Lack of complete validation and case sensitive

Computationally expensive and limited sampling

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

Fitness functions Consensus docking scoring, ADMET lters

Large fragment spaces with up to several thousand fragments

Statistically biasing the growth of molecules with desired features

A tree search algorithm

QXP scores together with the overall fragment scores

Linking predocked fragments by SEED

A genetic algorithm and a tabu search

Medicinal Research Reviews DOI 10.1002/med

r SHENG AND ZHANG

Table II. Continued

Combines multiobjective evolutionary techniques with graph theory

LIQUID fuzzy pharmacophore function

Fragment linking and docking

Binding afnity score and articial neural network

R-tree index and k-nearestneighbor search Evolutionary algorithm

Scaffold hopping or substructure optimization

Growing and linking

Medicinal Research Reviews DOI 10.1002/med

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

Alignment of fragments to the pharmacophore hypothesis

r SHENG AND ZHANG

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG

r SHENG AND ZHANG

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

Medicinal Research Reviews DOI 10.1002/med

r SHENG AND ZHANG

Table III. Continued

Medicinal Research Reviews DOI 10.1002/med

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

Medicinal Research Reviews DOI 10.1002/med

r SHENG AND ZHANG

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG

Medicinal Research Reviews DOI 10.1002/med

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG

Fragment-based optimization of triazole antifungal agents.

FRAGMENT INFORMATICS AND COMPUTATIONAL FBDD

r SHENG AND ZHANG