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Structural Bioinformatics in Drug Discovery.ppt
- 1. Structural Bioinformatics in DrugDiscovery Melissa Passino
- 2. Structural Bioinformatics • Whatis SBI? “Structural bioinformatics is a subset of bioinformatics concerned with the use of biological structures – proteins, DNA, RNA, ligands etc. and complexes thereof to further our understanding of biological systems.” http://biology.sdsc.edu/strucb.html
- 3. SBI in DrugDesign and Discovery • SBI can be used to examine: • drug targets (usually proteins) • binding of ligands ↓ “rational” drug design (benefits = saved time and $$$)
- 4. Traditional Methods ofDrug Discovery natural (plant-derived) treatment for illness/ailments ↓ isolation of active compound (small, organic)
- 5. synthesis of compound ↓ manipulation of structureto get better drug (greater efficacy, fewer side effects) Aspirin
- 6. Modern Methods ofDrug Discovery What’s different? • Drug discovery process begins with a disease (rather than a treatment) • Use disease model to pinpoint relevant genetic/biological components (i.e. possible drug targets)
- 7. Modern Drug Discovery disease→ genetic/biological target ↓ discovery of a “lead” molecule - design assay to measure function of target - use assay to look for modulators of target’s function ↓ high throughput screen (HTS) - to identify “hits” (compounds with binding in low nM to low μM range)
- 8. Modern Drug Discovery smallmolecule hits ↓ manipulate structure to increase potency i.e. decrease Ki to low nM affinity ↓ *optimization of lead molecule into candidate drug* fulfillment of required pharmacological properties: potency, absorption, bioavailability, metabolism, safety ↓ clinical trials
- 9. Interesting facts... • Over90% of drugs entering clinical trials fail to make it to market • The average cost to bring a new drug to market is estimated at $770 million
- 10. Impact of StructuralBioinformatics on Drug Discovery Genome Gene Protein HTS Hit Lead Candidate Drug Genomics Bioinformatics Structural Bioinformatics Chemoinformatics Structure-based Drug Design ADMET Modelling • Speeds up key steps in DD process by combining aspects of bioinformatics, structural biology, and structure-based drug design Fig 1 & 2 Fauman et al.
- 11.
- 12. human genome polysaccharides lipidsnucleic acids proteins Problems with toxicity, specificity, and difficulty in creating potent inhibitors eliminate the first 3 categories...
- 13. human genome polysaccharides lipidsnucleic acids proteins proteins with binding site “druggable genome” = subset of genes which express proteins capable of binding small drug-like molecules
- 14. Relating druggable targets todisease... GPCR STY kinases Zinc peptidases Serine proteases PDE Other 110 families Cys proteases Gated ion- channel Ion channels Nuclear receptor P450 enzymes Analysis of pharm industry reveals: • Over 400 proteins used as drug targets • Sequence analysis of these proteins shows that most targets fall within a few major gene families (GPCRs, kinases, proteases and peptidases) Fig. 3, Fauman et al.
- 15. Assessing Target Druggability •Once a target is defined for your disease of interest, SBI can help answer the question: Is this a “druggable” target? • Does it have sequence/domains similar to known targets? • Does the target have a site where a drug can bind, and with appropriate affinity?
- 16. Other roles forSBI in drug discovery • Binding pocket modeling • Lead identification • Similarity with known proteins or ligands • Chemical library design / combinatorial chemistry • Virtual screening • *Lead optimization* • Binding • ADMET
- 17. SBI in cancertherapy: MMPIs
- 18. • Inability tocontrol metastasis is the leading cause of death in patients with cancer (Zucker et al. Oncogene. 2000, 19, 6642-6650.) • Matrix metalloproteinase inhibitors (MMPIs) are a newer class of cancer therapeutics • can prevent metastasis (but not cytotoxic); may also play role in blocking tumor angiogenesis (growth inhibition) • Used to treat “major” cancers: lung, GI, prostate
- 19. What is anMMP? • Family of over 20 structurally related proteinases • Principal substrates: • protein components of extracellular matrix (collagen, fibronectin, laminin, proteoglycan core protein) • Functions: • Breakdown of connective tissue; tissue remodeling • Role in cancer: • Increased levels/activity of MMPs in area surrounding tumor
- 20. Brown PD. BreastCancer Res Treat 1998, 52, 125-136.
- 21. Whittaker et al.Chem. Rev. 1999, 99, 2735-2776
- 22. MMP-1,3,8 MMP-2 MMP-7 MMP-9 MMP-10 to 13,19,20 MMP-14 to17 Whittaker et al. Chem. Rev. 1999, 99, 2735-2776
- 23. Whittaker et al.Chem. Rev. 1999, 99, 2735-2776 “metallo” in MMP = zinc → catalytic domain contains 2 zinc atoms MMP catalysis
- 24. Peptidic inhibitors • Structurebased design – based on natural substrate collagen – zinc binding group • Poor Ki values, not very selective (inhibit other MPs) Brown PD. Breast Cancer Res Treat 1998, 52, 125-136.
- 25. Peptidic hydroxamate inhibitors •Specificity for MMPs over other MPs • Better binding (low nM Ki) • But poor oral bioavailability
- 26. A (not very)long time ago, in a town (not too) far away… …lived a company named Agouron… …and this company had a dream, a dream to design a nonpeptidic hydroxamate inhibitor of MMPs…
- 27. ...so they madesome special crystals… used x-ray crystallography/3D structure of recombinant human MMPs bound to various inhibitors ↓ to determine key a.a. residues, ligand substituents needed for binding Gelatinase A http://www.rcsb.org/pdb/
- 28. …and used themagic of structural bioinformatics to design many, many nonpeptidic hydroxylates. oral bioavailabity Ki anti- growth anti- metastasis repeat…
- 29. Results… AG3340 “Prinomastat” • Good oral bioavailability •Selective for specific MMPs – may implicate their roles in certain cancers
- 30. Prinomastat • Evidence showingprevention of lung cancer metastasis in rat and mice models • Clinical trials → non small cell lung cancer → hormone refractory prostate cancer …stopped at Phase 3 (Aug 2000) because did not show effects against late stage metastasis
- 31. Morals of thestory… • SBI can be used as basis for lead discovery and optimization • MMPs are good targets for chemotherapy to help control metastasis… …but MMPIs must be combined with other cytotoxic drugs to get maximum benefits, and used at earliest stage possible