1. Asia’s Largest Global Software & Services Company Genomes to Drugs: A Bioinformatics Perspective Sharmila Mande Bioinformatics Division Advanced Technology Centre

2. Asia’s Largest Global Software & Services Company Data types along the drug discover chain Lead Optimisation Pre-clinical trials Target Validation Target Identification Genomics SNP EST/cDNA Gene expression Proteomics Chemistry HTS ADMET SNP

3. 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

4. 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

5. Asia’s Largest Global Software & Services Company Design principles Do experiments in silico first Synthesis “Real World” Bioassay Selection Analysis “in silico World” Hypothesis

6. 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

7. 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

8. 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

9. 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

10. Asia’s Largest Global Software & Services Company Target Validation There is an opportunity to identify many more targets Bottleneck in validation of drug targets

11. 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

12. Asia’s Largest Global Software & Services Company Drug Design Cycle

13. Asia’s Largest Global Software & Services Company Computational Approaches in Drug Design: No prior knowledge of receptor structure Combinatorial Chemistry

14. Asia’s Largest Global Software & Services Company Cyclic urea inhibitor of HIV protease from pharmacophore hypothesis. Pharmacophore generation

15. 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

16. Asia’s Largest Global Software & Services Company Examples of Structure Based Drug Design HIV protease with amprenavir Influenza with neuraminidase inhibitor

17. 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 6% in computer-based approach

18. Asia’s Largest Global Software & Services Company Lead Optimization Enzyme active site Ki~1mM Ki~1-10 nM Receptor / Enzyme Receptor/ Enzyme Receptor / Enzyme

19. Asia’s Largest Global Software & Services Company ADMET Drug failures 39% Poor pharmacokinetics 11% Toxicity ADMET prediction in-silico approaches

20. Asia’s Largest Global Software & Services Company In silico ADMET Identify Non soluble compounds Non permeable compounds Non metabolically stable compounds Toxicophores

21. 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

22. 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

23. Asia’s Largest Global Software & Services Company Thank You