Presentation on theme: "Structural Bioinformatics in Drug Discovery"— Presentation transcript:
1Structural Bioinformatics in Drug Discovery Melissa Passino
2Structural Bioinformatics What is 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.”
3SBI in Drug Design and Discovery SBI can be used to examine:drug targets (usually proteins)binding of ligands↓“rational” drug design(benefits = saved time and $$$)
4Traditional Methods of Drug Discovery natural(plant-derived) treatment for illness/ailments↓isolation of active compound(small, organic)
5manipulation of structure to get better drug synthesisof compound↓manipulation of structure to get better drug(greater efficacy,fewer side effects)Aspirin
6Modern Methods of Drug Discovery NEW and IMPROVED!What’s different?Drug discovery process beginswith a disease (rather than a treatment)Use disease model to pinpoint relevant genetic/biological components (i.e. possible drug targets)
7discovery of a “lead” molecule Modern Drug Discoverydisease → genetic/biological target↓discovery of a “lead” molecule- design assay to measure function of target- use assay to look for modulators of target’s functionhigh throughput screen (HTS)- to identify “hits” (compounds with binding in low nM to low μM range)
8Modern Drug Discovery small molecule hits ↓ manipulate structure to increase potencyi.e. decrease Ki to low nM affinity*optimization of lead molecule into candidate drug*fulfillment of required pharmacological properties:potency, absorption, bioavailability, metabolism, safetyclinical trials
9Interesting facts...Over 90% of drugs entering clinical trials fail to make it to marketThe average cost to bring a new drug to market is estimated at $770 million
10Impact of Structural Bioinformatics on Drug Discovery Fig 1 & 2Fauman et al.Speeds up key steps in DD process by combining aspects of bioinformatics, structural biology, and structure-based drug design
12human genomepolysaccharidesnucleic acidsproteinslipidsProblems with toxicity, specificity, and difficulty in creating potent inhibitors eliminate the first 3 categories...
13proteins with binding site human genomepolysaccharidesnucleic acidsproteinslipidsproteins with binding site“druggable genome” = subset of genes which express proteins capable of binding small drug-like molecules
14Relating druggable targets to disease... Analysis of pharm industry reveals:Over 400 proteins used as drug targetsSequence 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.
15Is this a “druggable” target? Assessing Target DruggabilityOnce 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?
16Other roles for SBI in drug discovery Binding pocket modelingLead identificationSimilarity with known proteins or ligandsChemical library design / combinatorial chemistryVirtual screening*Lead optimization*BindingADMET
18Used to treat “major” cancers: lung, GI, prostate Inability to control metastasis is the leading cause of death in patients with cancer (Zucker et al. Oncogene. 2000, 19, )Matrix metalloproteinase inhibitors (MMPIs) are a newer class of cancer therapeuticscan prevent metastasis (but not cytotoxic); may also play role in blocking tumor angiogenesis (growth inhibition)Used to treat “major” cancers: lung, GI, prostate
19What is an MMP? 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 remodelingRole in cancer:Increased levels/activity of MMPs in area surrounding tumor
20Brown PD. Breast Cancer Res Treat 1998, 52, 125-136.
22Whittaker et al. Chem. Rev. 1999, 99, 2735-2776 MMP-1,3,8MMP-2MMP-7MMP-10 to 13,19,20MMP-9Whittaker et al. Chem. Rev. 1999, 99,MMP-14to 17
23Whittaker et al. Chem. Rev. 1999, 99, 2735-2776 MMP catalysis“metallo” in MMP = zinc→ catalytic domain contains 2 zinc atomsWhittaker et al. Chem. Rev. 1999, 99,
24Brown PD. Breast Cancer Res Treat 1998, 52, 125-136. Peptidic inhibitorsStructure based designbased on natural substrate collagenzinc binding groupPoor Ki values, not very selective (inhibit other MPs)Brown PD. Breast Cancer Res Treat 1998, 52,
25Peptidic hydroxamate inhibitors Specificity for MMPs over other MPsBetter binding (low nM Ki)But poor oral bioavailability
26A (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 made some 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 bindingGelatinase A
28…and used the magic of structural bioinformatics to design many, many nonpeptidic hydroxylates. oral bioavailabityanti-metastasisanti-growthKirepeat…
29Results… AG3340 “Prinomastat” Good oral bioavailability Selective for specific MMPsmay implicate their roles in certain cancers
30PrinomastatEvidence showing prevention of lung cancer metastasis in rat and mice modelsClinical 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
31Morals of the story…SBI can be used as basis for lead discovery and optimizationMMPs 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