Pharm 202

Computer Aided Drug Design

Phil Bourne
bourne@sdsc.edu
http://www.sdsc.edu/pb -> Courses -> Pharm 202

Several slides are taken from UC Berkley Chem 195

 Perspective

Principles of drug discovery (brief)

Computer driven drug discovery
Data driven drug discovery
Modern target identification and selection
Modern lead identification

Overall strong structural bioinformatics emphasis

 What is a drug?
Defined composition with a pharmacological
effect
Regulated by the Food and Drug
Administration (FDA)
What is the process of Drug Discovery and
Development?
Drugs and the Discovery Process
Small Molecules
Natural products
fermentation broths
plant extracts
animal fluids (e.g., snake venoms)
Synthetic Medicinal Chemicals
Project medicinal chemistry derived
Combinatorial chemistry derived
Biologicals
Natural products (isolation)
Recombinant products
Chimeric or novel recombinant products
 Discovery vs. Development
Discovery includes: Concept, mechanism,
assay, screening, hit identification, lead
demonstration, lead optimization
Discovery also includes In Vivo proof of
concept in animals and concomitant
demonstration of a therapeutic index
Development begins when the decision is
made to put a molecule into phase I clinical
trials
 Discovery and Development
The time from conception to approval of a
new drug is typically 10-15 years
The vast majority of molecules fail along
the way
The estimated cost to bring to market a
successful drug is now $800 million!!
(Dimasi, 2000)
 Drug Discovery Processes Today
Physiological
Hypothesis

Primary Assays
Molecular Biochemical
Biological Cellular
Hypothesis Pharmacological
Physiological Initial Hit
(Genomics)
Screening Compounds
+
Sources of Molecules
Chemical Natural Products
Hypothesis Synthetic Chemicals
Combichem
Biologicals
 Drug Discovery Processes - II

Hit to Lead
Secondary Chemistry
Evaluation - physical
- Mechanism properties
Of Action -in vitro
- Dose Response metabolism
Initial Hit
Compounds

Initial Synthetic First In Vivo

Evaluation Tests
- analytics - PK, efficacy,
- first analogs toxicity
 Drug Discovery Processes - III

Lead Optimization

Potency
Selectivity Pharmacology
Physical Properties Multiple In Vivo
Development
PK Models Candidate
Metabolism
Oral Bioavailability Chronic Dosing (and Backups)
Synthetic Ease Preliminary Tox
Scalability
 Drug Discovery Disciplines
Medicine
Physiology/pathology
Pharmacology
Molecular/cellular biology
Automation/robotics
Medicinal, analytical,and combinatorial
chemistry
Structural and computational chemistries
Bioinformatics
Drug Discovery Program Rationales
Unmet Medical Need
Me Too! - Market - ($$$s)
Drugs in search of indications
Side-effects often lead to new indications
Indications in search of drugs
Mechanism based, hypothesis driven,
reductionism
 Serendipity and Drug Discovery
Often molecules are discovered/synthesized
for one indication and then turn out to be
useful for others
Tamoxifen (birth control and cancer)
Viagra (hypertension and erectile dysfunction)
Salvarsan (Sleeping sickness and syphilis)
Interferon-a (hairy cell leukemia and Hepatitis C)
 Issues in Drug Discovery
Hits and Leads - Is it a Druggable target?
Resistance
Pharmacodynamics
Delivery - oral and otherwise
Metabolism
Solubility, toxicity
Patentability
 A Little History of Computer
Aided Drug Design

1960s - Viz - review the target - drug interaction

1980s- Automation - high trhoughput target/drug selection
1980s- Databases (information technology) - combinatorial
libraries
1980s- Fast computers - docking
1990s- Fast computers - genome assembly - genomic based
target selection
2000s- Vast information handling - pharmacogenomics
From the Computer Perspective
 Progress

About the computer industry

If the automobile industry had made as much

progress in the past fifty years, a car today
would cost a hundredth of a cent and go faster
than the speed of light.
Ray Kurzweil, The Age of Spiritual Machines
 Growth of pixel fill rates
1200

1000
F ill rate, Mp ixels/s

800

600
SGI PC cards
400

200
* Not counting
custom hardware
0 or special
1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001
configurations

Fill rates recently growing by

x2 every year Data source: Product literature
Comparing Growth Rates
40
Processor performance growth
35 Memory bus speed growth
Pixel fill rate growth
30
Increase factor

25

20

15

10

0
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
From the Target Perspective
 Bioinformatics - A Revolution

Biological Experiment Data Information Knowledge Discovery

Collect Characterize Compare Model Infer

Complexity Technology
Data
Higher-life 1 10 100 1000 100000 Computing
Power
Organ Brain Cardiac
Mapping Modeling

Cellular
Model Metaboloic
Pathway of E.coli
Sub-cellular 106 102 Neuronal 1
Modeling # People/Web Site

Assembly Virus Ribosome

Structure
Genetic
Circuits
Structure Human
Genome Yeast E.Coli C.Elegans 1 Small
Project Genome Genome Genome Genome/Mo.
ESTs Gene Chips Human Sequencing
Sequence Genome Technology
90 95 00 05
(C) Copyright Phil Bourne 1998
Year
The Accumulation of Knowledge
This molecular scene
for cAMP dependant
protein kinase (PKA)
depicts years of
collective knowledge.

Traditionally structure
determination has
been functional driven

As we shall see it is
becoming genomically
driven
 History
History
Strong sense of
community ownership

We are the current

custodians

The community
watches our every
move

The community
itself is changing
Status - Numbers and Complexity

(a) myoglobin (b) hemoglobin (c) lysozyme (d) transfer RNA

(e) antibodies (f) viruses (g) actin (h) the nucleosome
(i) myosin (j) ribosome
Courtesy of David Goodsell, TSRI
 The Structural Genomics Pipeline
(X-ray Crystallography)
Basic Steps
Crystallomics
Isolation,
Target Expression, Data Structure Structure Functional
Selection Purification, Collection Solution Refinement Annotation Publish
Crystallization

Bioinformatics Automation Automation Software integration Bioinformatics No?

Distant Bioinformatics Better Decision Support Alignments
homologs Empirical sources MAD Phasing Automated Protein-protein
Domain rules fitting interactions
recognition Protein-ligand
interactions
Motif recognition
Anticipated Developments
structure info sequence info Protein sequences
SCOP, PDB NR, PFAM
Prediction of :
signal peptides (SignalP, PSORT)
Building FOLDLIB: transmembrane (TMHMM, PSORT)
------------------------------------ coiled coils (COILS)
PDB chains
SCOP domains
low complexity regions (SEG)
PDP domains
CE matches PDB vs. SCOP
----------------------------------- Structural assignment of domains by
90% sequence non-identical PSI-BLAST on FOLDLIB-PRF
minimum size 25 aa
coverage (90%, gaps <30, ends<30) Only sequences w/out A-prediction

Structural assignment of domains by

123D on FOLDLIB-PRF
Only sequences w/out A-prediction
Create PSI-BLAST profiles
for FOLDLIB vs. NR Functional assignment by PFAM, NR,
PSIPred assignments

FOLDLIB-PRF
Domain location prediction by sequence

Store assigned
The Genome Annotation Pipeline regions in the DB
Example - http://arabidopsis.sdsc.edu
From the Drug Perspective
 Combinatorial Libraries

Thousands of variations to a fixed template

Good libraries span large areas of chemical and
conformational space - molecular diversity
Diversity in - steric, electrostatic, hydrophobic interactions...
Desire to be as broad as Merck compounds from
random screening
Computer aided library design is in its infancy

Blaney and Martin - Curr. Op. In Chem. Biol. (1997) 1:54-59

Statement of the Director, NIGMS, before the House Appropriations
Subcommittee on Labor, HHS, Education Thursday, February 25, 1999