asia’s largest global software & services company genomes to drugs: a bioinformatics...
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Asia’s Largest Global Software & Services Company
Genomes to Drugs: A Bioinformatics Perspective
Sharmila Mande
Bioinformatics Division
Advanced Technology Centre
Asia’s Largest Global Software & Services Company
Data types along the drug discover chain
Lead Lead
Optimisation Pre-clinical trials
Target
Validation
Target
Identification Identification
Genomics
SNP
EST/cDNA
Gene expression
Proteomics
Chemistry
HTS
ADMET
SNP
Asia’s Largest Global Software & Services Company
Traditional drug discovery process
• Development time per drug: 8 to 12 years.
• Development cost per drug: $500- $900 M
• High failure rates - especially in clinical stage
Asia’s Largest Global Software & Services Company
Post-genomics scenario
• Reduction of drug development time• Reduction of cost of developing drugs
– Develop high quality information early in drug discovery process
– Faster identification of new drug targets– Higher quality target and leads– Reduction of drug failure rates
Asia’s Largest Global Software & Services Company
Design principles
• Do experiments in silico first
Synthesis“Real World”
Bioassay
Selection Analysis
“in silico World”
Hypothesis
Asia’s Largest Global Software & Services Company
Whole genomes
• Complete genome sequences of – about 138 microbial organisms– Human– Parasites– Plant
• Possible to develop novel cures
Asia’s Largest Global Software & Services Company
Drug Target Identification
Three possible cases:
• Human protein is not functioning properly, or its activity needs to be modified.
Sickle cell anemia
• The potential target is a key protein from infectious organism, and has no counterpart in humans
Bacterial Cell wall
• The target is a protein from an infectious organism and a homologous protein exists in humans.
DHFR
Asia’s Largest Global Software & Services Company
How Many Drug Targets ?
• Present day therapy addresses only 500 molecular targets
• Cell membrane receptors constitute the largest class of current drug targets
• Human and other microbial genomes suggest that many more targets may be available
Asia’s Largest Global Software & Services Company
Target Identification: Comparative Genomics
• Target identification in the pre-genomics era was an extremely tedious and time consuming process.
• Genomics approaches - a major development in recent times in drug discovery
e.g. broad spectrum antibiotics
drugs against malaria parasite
Asia’s Largest Global Software & Services Company
Target Validation
• There is an opportunity to identify many more targets
• Bottleneck in validation of drug targets
Asia’s Largest Global Software & Services Company
Computational Approaches in Drug Design
without prior knowledge of receptor structure
Generation of a pharmacophore
3D arrangement of functionally important parts of molecules
Quantitative structure-activity relationships
with prior knowledge of receptor structure
Docking
Scan a database for optimal fitting of inhibitors
De-novo design
Generate a “custom” ligand for a given active site
Asia’s Largest Global Software & Services Company
Drug Design Cycle
Asia’s Largest Global Software & Services Company
Computational Approaches in Drug Design: No prior knowledge of receptor structure
Combinatorial Chemistry
Asia’s Largest Global Software & Services Company
Cyclic urea inhibitor of HIV protease from pharmacophore hypothesis.
Pharmacophore generation
Asia’s Largest Global Software & Services Company
Computational Approaches in Drug Design: Prior knowledge of receptor structure
• Captopril, the first therapeutic drug from structure based studies
• Antihypertensive
• Angiotensin converting enzyme modelled on carboxypeptidase
• 30,000 fold improvement in inhibitory activity obtained, from the first lead N-succinoyl-prolin to captopril
Asia’s Largest Global Software & Services Company
Examples of Structure Based Drug Design
HIV protease with amprenavir
Influenza with neuraminidase inhibitor
Asia’s Largest Global Software & Services Company
If HTS is available, why do docking at all?
Protein Tyrosine Phosphatase 1B inhibitors:
• 400,000 compounds screened by HTS vs. 365 compounds high scoring docking compounds.
• Hit-rate by computational approaches 1700 times higher. Computationally identified compounds more “drug-like”.
Dihydropicolinate reductase inhibitor:
• hit rate < 0.2% in HTS and > 6% in computer-based approach
Asia’s Largest Global Software & Services Company
Lead Optimization
Enzyme Enzyme Enzyme
active site
Ki~1mMKi~1-10 nM
Receptor/Enzyme
Receptor/Enzyme
Receptor/Enzyme
Asia’s Largest Global Software & Services Company
ADMET
Drug failures
• 39% Poor pharmacokinetics
• 11% Toxicity
ADMET prediction
• in-silico approaches
Asia’s Largest Global Software & Services Company
In silico ADMET
Identify• Non soluble compounds• Non permeable compounds• Non metabolically stable compounds• Toxicophores
Asia’s Largest Global Software & Services Company
Bioinformatics success stories
• Quick target identification (Merck)– potential drug targets for schizophrenia
• Expedited drug candidate identification (SKB)– drugs for bone tumor (target cathepsin K)
• Poor drug candidate elimination (Aventis vs GSK and SP)– anti IL-5 therapy against asthma
Asia’s Largest Global Software & Services Company
• Part of Advanced Technology Centre
• 40 persons (9 Ph.D’s)
• Undertaking R&D in selected areas of computational biology
TCS’ Bioinformatics Division
3D Modelling
Drug Design
Sequence Analysis
Structural Analysis
Structural Manipulations
Simulation
TCS
Bio-Suite
Genome Analysis
Comparative Genomics
Asia’s Largest Global Software & Services Company
Thank You
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