Omics revolution

• Bioinformatics: alive and kicking

• “Bioinformatics has become too central to biology to
be left to specialist bioinformaticians. Biologists are
all bioinformaticians now”

physicoinformatics’

Bioinformaticians: gone by 2012

Bioinformatics: stronger than ever

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Lincoln D Stein; Genome Biology 2008, 9:114
 Much About Structure

• Structure Function
• Structure Mechanism
• Structure Origins/Evolution
• Structure-based Drug Design
 Strategies of Molecular Modeling

Ligand Based Structure Based

SAR, 2D,
3D-QSAR Crystal structure Homology
analysis Modeling
Lead Identification
Computational analysis of Protein-ligand
interactions

In silico ADMET Fragment based Ligand modifications for

better affinity

Lead Optimization
Phramacophore model

Database screening

Prioritization of Hits
 Ligand (analog)
Target (structure) based drug design
based drug design
Receptor structure is not
Receptor structure is known
known
Mechanism is known/
Mechanism is known unknown

Ligands and their Ligands and their biological

biological activities are activities are known
known/ unknown
 Structural Bioinformatics in Drug Discovery

Homology
modeling of
target protein
Target Confirm
protein Virtual library of Large using Crystallo-
sequence compounds or scale graphy, Kinetic
QSAR analysis Docking analysis
Crystal
structure of
target
protein

Lead Compound
identification development
& Lead (Drug)
optimization

Schematic outline of the application of Structural bioinformatics and Protein

crystallography (structural molecular biology) in drug discovery process.
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Some recent examples of the application of Structural Bioinformatics using
homology modeling technique in drug discovery projects:

Homology modelled Active site Importance of theoretically

S.No protein prediction (homology) modelled protein
(Docking, Virtual
screening,
Synthesis)
1. Cyclin-dependent Docked diarylurea CDK4 homology model
kinase 4 (CDK4) class of compounds. guided design of potent N-(9-
oxo-9H-fluoren-4-yl)-N'-
pyridin-2-yl urea compound,
further validated by
crystallographic method.
2. DNA Designed a novel N4-fluoroacetyl-5-azacytidine
methyltransferase 1 derivative of the compound functioned as an
known DNA efficient inhibitor of DNA
methyl- transferase methylation in human tumor
inhibitor 5- cell lines and also provides
azacytidine. novel opportunities for
pharmacological applications.
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3. Thrombin- Imidazole acetic Homology modeling of TAF
activatable acid inhibitors lead to the identification of its
fibrinolysis (TAF) synthesized and potent and selective
tested. inhibitors.
4. IKCa 1 Charybdotoxin and Provided strong evidence for
(Intermediate its analogs docked. topological similarity of the
conductance (This compound external vestibules of diverse
calcium-activated blocks voltage gated K(+) channels and
potassium channel channels) demonstrates the feasibility of
protein 1) using structure-based
strategies to design selective
inhibitors for mammalian
K(+) channels.
5. SARS-CoV MPro AG7088 docked Anti-SARS activity in vitro
into the substrate was confirmed for AG7088.
binding site of Derivatives of AG7088
SARS-CoV MPro showed better kinetic values.

Ref: Alexander H, Luis F P and Rolf H (2004) Drug Discovery Today 9: 659-669 7
DRUGS DEVELOPED FROM STRUCTRE-BASED APPROACHES
IN THE MARKET

Captopril Hypertension 1981 Bristol-Mayers

Dorzolamide Glaucoma 1995 Merck

Imatinib Leukaemia 2001 Novartis

Erlotinib Lung Cancer 2004 OSI & Genetech

Lopinavir AIDS 2000 Abbott

Amprenavir AIDS 1999 Vertex & GSK

Nelfinavir AIDS 1999 Pfizer & Lilly

Zanamivir Influenza 1999 GlaxoSmithKilne8