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Pathogen Protein-Protein Interactions (F Modeling and Determining the Structures of Proteins and Macromolecular Assemblies Andrej Sali http://salilab.org/ Depts. of Biopharmaceutical Sciences and Pharmaceutical Chemistry UC California Institute for Quantitative Biomedical Research SF University of California at San Francisco 06/01/2006 Topics 1. Tropical Disease Initiative (TDI) (S. Maurer, A. Rai) 2. Automated, large-scale comparative modeling for: • drug target selection via binding site analysis (J. Overington, B. Al-Lazikani, Inpharmatica Inc.) • drug target selection and hit generation via virtual screening (B. Shoichet) • drug target selection via bioinformatics annotation (D. Roos) 3. Identification of host - pathogen protein interactions for: • drug target selection (J. McKerrow, J. DeRisi, E. Stebbins, N. Krogan, ...) 06/01/2006 Topics 1. Tropical Disease Initiative (TDI) (S. Maurer, A. Rai) 2. Automated, large-scale comparative modeling for: • drug target selection via binding site analysis (J. Overington, B. Al-Lazikani, Inpharmatica Inc.) • drug target selection and hit generation via virtual screening (B. Shoichet) • drug target selection via bioinformatics annotation (D. Roos) 3. Identification of host - pathogen protein interactions for: • drug target selection (J. McKerrow, J. DeRisi, E. Stebbins, N. Krogan, ...) 06/01/2006 Tropical Disease Initiative An open source approach to drug discovery www.tropicaldisease.org http://nurture.nature.com/wikis/tdi/ http://www.thesynapticleap.org S. Maurer, A. Rai, A. Sali. Finding Cures for Tropical Diseases: Is Open Source an Answer? PLoS Medicine 1, 180-184, 2004. Collaborative Drug Discovery The Economist, June 10, 2004. http://www.collaborativedrug.com 4 Tropical Disease Initiative An open source approach to drug discovery www.tropicaldisease.org databases of genome sequences S. Maurer, A. Rai, A. Sali. Finding Cures for Tropical Diseases: Is Open Source an Answer? database of protein structures PLoS Medicine 1, 180-184, 2004. virtual ligand libraries PubMed, journals other databases sequence similarity searches protein structure modeling literature searches protein-ligand docking VIRTUAL functional annotation COMPUTING PHARMA and other development leads organizations TOXICITY AND TDI PHARMACOKINETIC TARGET DISCOVERY EVALUATION LEAD DISCOVERY LEAD OPTIMIZATION CLINICAL STUDIES DRUG PRODUCTION synthetic chemistry compound libraries high-throughput screening CHEMISTRY ugs protein production protein engineering dr substrate specificity studies structural biology target validation BIOLOGY 5 Public Databases PubChem InterPro PIR & MLI ProDom Sequence Compounds GenBank SMART ZINC TrEMBL DBAli PFam SCOP DALI UniProt PDB ProSite CATH Function Structure EnZyme MODBASE SFLD DIP PIBASE SNPBase LS-SNP 6 The Universe of Protein-Ligand Interactions Center for Computational Proteomics Research (CCPR) All known protein structures All known protein sequences Comparative modeling Protein-Protein Docking Pipeline The California Institute for Ligand-Protein Refine protein models All known protein interactions Quantitative Biomedical Docking Pipeline Research (QB3) Identify ligand Identify protein Patsy Babbitt, Ken Dill, Tom Lists of small ligands binding sites on models binding sites on models Ferrin, John Irwin, Matt Jacobson, Tanja Kortemme, Tack Kuntz, Marc A. Marti- Virtual ligand libraries Annotated Renom, Andrej Sali, Brian protein structure models Shoichet Build ligand-protein Build protein-protein complexes complexes http://www.ccpr.ucsf.edu/ Rescore ligand-protein Specificity modeling of complexes protein interactions Central database Graphical User Interface 7 TDI web site projects: Collaboration tools Prince Felipe Research Center Gene Cards Valencia, Spain Marc Marti-Renom Gene Basket Gene Annotation Structure Prediction Ginger Taylor Target Selection for Structural Genomics Database of annotated chemical compounds Collaborative Drug Discovery Barry Bunin www.tropicaldisease.org 8 OJECT Gene Cards PR collecting gene information As of September 2005, the Malaria genome had 5,270 ORFs. • NCBI at http://www.ncbi.nlm.nih.gov/ • BioMart at http://www.biomart.org/ • ModBase at http://www.salilab.org/modbase Literature Annotation Structure Function 9 OJECT Gene Basket PR add content to your genes... add genes to your content TSL registered users will be able to save gene cards in their baskets and associate pieces of information to entries in the basket. For example, a user may be browsing the literature at PubMed and find an interesting article, with just one click the system should be able to propose and association between the article and any of the genes in his/her basket. As seen on: 10 OJECT Gene Basket PR add content to your genes... add genes to your content TSL registered users will be able to save gene cards in their baskets and associate pieces of information to entries in the basket. For example, a user may be browsing the literature at PubMed and find an interesting article, with just one click the system should be able to propose and association between the article and any of the genes in his/her basket. As seen on: 10 QB3 Neglected Disease Symposium Speaker Biographies Victoria Hale, Ph.D., Founder, Chief Executive Officer and Chair of the Board of Directors. Dr. Hale established her expertise in all stages of biopharmaceutical drug development at the US Food and Drug Administration (FDA), Center for Drug Evaluation and Research; at Genentech, Inc., the world's first biotechnology company; and as Co-founder and Chief Scientific Officer of Axiom BioMedical, Inc., a pharmaceutical development and liability consultancy. She presently maintains an Adjunct Associate Professorship in Biopharmaceutical Sciences at the University of California, San Francisco (UCSF), is an Advisor to the World Health Organization (WHO) for building ethical review capacity in the developing world, and has served as an expert reviewer to the National Institutes of Health (NIH) on the topic of biodiversity. Dr. Hale and OneWorld Health were recently included in the Scientific American 50, the magazine’s annual list recognizing outstanding acts of leadership in science and technology from the past year (2004). She was also named one of 2004's “Most Outstanding Social Entrepreneurs” by the Schwab Foundation for Social Entrepreneurship in Switzerland and selected as a Leadership Foundation Fellow of the International Women's Forum in September 2003. Dr. Hale earned her Ph.D. in Pharmaceutical Chemistry from UCSF. Shirley Luckhart, Ph.D. Associate Professor, University of California, Davis. General areas of research in the laboratory include: the molecular cell biology and biochemistry of the interaction between malaria parasites and their mosquito hosts, the functional characterization of primitive orthologs of mammalian innate immune molecules and cell signaling proteins using the mosquito as an invertebrate model. Specific research projects include: characterization of mosquito gene products that inhibit malaria and its application to comparative protparasiteein stru cdevelopmture predientctio andn. He mo islecular/ involvedbiochem in theical analysis of parasite Tropical Disease Initiativedamage ;for sig anna lopen-source transduction approach pathway sto in drugvolv edevelopmd in parasiteent. induction Dr Marti- of mosquito innate OJECT GeneRenom was appoinimmunity;ted Res earc analysisBasketh Assoc ofiat expression,e at the Laboratory signaling, of andMolecular regulation Biophysics of anti-parasite genes in (Sali Lab) at The Rockefellermosquitoes University; molecula rin a n2d0 0fu2n. c Htioen realc aenivaelyds heiss ofBS immunec in Ge nfacetitcorss fro thatm are conserved PR the Autonomous Universitybetween mofo squitoesBarcelona, and Ca theirtalonia, mammalia in 1994n andhosts; a PhDimmunological in Biophysics crosstalk in between add content to your1999, focusing genes... on themosquitoes developm andent m ofadda mmamethodsls at f theogenesr finolterfaceding st uofd ibloodfeeding.es u sitong mo leyour cular content dynamics. Jim Wells receiveMad ar Bc .AA .Ma degrtire-Re ienn boimoc ihse Amdisjturnyc ftr Aomss itshtea nt Professor at the University of CaliDfoernpairat,m Beenrkeley,ts of B iandoph ar Ph.D.maceu degreetical Sc inie nces and Pharmaceutical biochemistry fromC hWemasihsitnryg taonnd S tthaet eC Ualnifivoernrsiait yIn. s Htitiust pe ofsotrd Qocutaonratilt ative Biomedical studies were doneResearch at Stanford at theUniv Universersity iMedicalty of Califor School,nia atDepartm San Francisco.ent Most of his of Biochemistry. currenDr. Wellst work was involves the founding improving member the accuracyof the Protein of protein 3-D models, Engineering Departmfocuesntin gat o Genentech,n sequence sInctru cwhereture a lheig nworkedment m foreth o16ds . Recently, his years. His researchinterest focused has on been de signingfocused new on unders functionaltanding properties protein structure evolution into enzymes and hormones and developing new technologies for engineering proteins. In 1998, Dr. Wells founded Sunesis Pharmaceuticals where he served as President and Chief Scientific Officer and developed a novel fragment malaria infections, and studiesdiscovery of mole technologycular mechanism known as disulfides of drug trapping resistance. or Tethering. Dr. In 2005, Dr. Wells joined UCSF as the Harry W. and Diana Hind Distinguished Professor in Pharmaceutical Rosenthal is on the editorial boardsScienc eofs. HAntie is am joiicrobialnt Profess Agentsor in the D andepar tmChements ofot Cherapyellular & Mandole cTheular
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