INTERACTOMICS RAM SAMUDRALA ASSOCIATE PROFESSOR UNIVERSITY OF WASHINGTON NIH DIRECTOR’S PIONEER AWARD 2010 How does the genome of an organism specify its.

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INTERACTOMICS RAM SAMUDRALA ASSOCIATE PROFESSOR UNIVERSITY OF WASHINGTON NIH DIRECTOR’S PIONEER AWARD 2010 How does the genome of an organism specify its behaviour and characteristics? How can we use this information to improve human health and quality of life? COMPUTATIONAL ANALYSIS OF NOVEL DRUG OPPORTUNITIES THE CANDO TEAM cando.compbio.washington.edu

GENOME SEQUENCE TO PROTEIN AND PROTEOME… STRUCTUREFUNCTION SYSTEMS INFRASTRUCTURE APPLICATIONS EVOLUTION THERAPEUTICS NANOTECHNOLOGY RICE DESIGN INTERACTION COMPOUND DNA/RNAPROTEIN

SHOTGUN DRUG REPURPOSING ALL KNOWN DRUGS (~5,000 FROM FDA) ALL TARGETS WITH KNOWN STRUCTURE (~80,000+) + FRAGMENT BASED DOCKING WITH DYNAMICS (~120,000,000) PRIORITISED HITS MACHINE LEARNING M Lagunoff (UW), W Van Voorhis (UW), S Michael (FCGU), J Mullins (UW), G Wong/A Mason/L Tyrell (U Alberta), W Chantratita/P Palittapongarnpim (Thailand) Many more at cando.compbio.washington.edu herpes, malaria, dengue hepatitis C, dental caries HIV, HBRV, XMRV, rabies, encephalitis, cholera, tuberculosis, various cancers, and many more: cando.compbio.washington.edu CLINICAL STUDIES/APPLICATION INITIAL CLINICAL TRIALS IN VITRO STUDIES IN VIVO STUDIES DISSOCIATION CONSTANTS (KD) (~ collaborations)

Multitarget protocol: 2,344 → 16 → 6 ≤ 1 µM ED50 HTS protocol: 2,687 → 19 ≤ 1 µM ED50 HTS protocol: 2,160 → 36 ≤ 1 µM ED50 Docking protocol: 355,000 → 100 → 1 ≤ 10 µM ED50 Docking protocol: 241,000 → 84 → 4 ≤ 10 µM ED50 14 targets MALARIA Trends in Pharmacological Sciences, DENGUE PLoS Neglected Tropical Diseases, /4 ≤ µM ED50 against dengue virus Prediction #1 Prediction #2 Viral E protein PROSPECTIVE PRELIMINARY VERIFICATION Observed: Function is inactivated. KD protease ligand ≤ μM KD protease dimer ≤ μM Experiment 1 Experiment 2 HERPES (HSV, CMV, KSHV) Predicted protease (dimer) + inhibitor: Herpes viral load Lagunoff/ Van Voorhis/ Michael

NEISSERIA MENINGITIDIS factor H binding protein from Neisseria meningitidis mimics host carbohydrates and recruits host factor H to protect against the complement immune response Neisseria meningitidis factor H binding protein Homo sapiens factor H Schneider et al. Nature, Topamax Treatement of epilepsy Voacamine Anti malarial agent Loop movement breaks the interface Chopra/White

ACKNOWLEDGEMENTS Adrian Laurenzi Brian Buttrick Emilia Gan Ersin Emre Oren Gaurav Chopra George White Haychoi Taing Helen Yu Hernan Zamalloa Jason North Jeremy Horst Ling-Hong Hung Matthew Clark Manish Michael Zhou Nalini Schaduangat Omid Zarei Raymond Zhang Sai Paul Sergey Ovchinnikov Thomas Wood Current group members: Aaron Chang Aaron Goldman Brady Bernard Chuck Mader Cyrus Hui David Nickle Duangdao Wichadukul Duncan Milburn Ekachai Jenwitheesuk Gong Cheng Imran Rashid Jason McDermott Juni Lee Kai Wang Marissa LaMadrid Michael Inouye Michael Shannon Michal Guerquin Nipa Jongkon Past group members: Rob Braiser Renee Ireton Shu Feng Sarunya Suebtragoon Shing-Chung Ngan Shyamala Iyer Siriphan Manocheewa Somsak Phattarasukol Stewart Moughon Tianyun Liu Vanessa Steinhilb Vania Wang Weerayuth Kittichotirat Yi-Ling Cheng Zach Frazier CANDO TEAM MEMBERS IN BLUE: CURE OR TREAT DISEASES CURRENTLY UNTREATED

ACKNOWLEDGEMENTS Funding agencies: National Institutes of Health National Science Foundation -DBI -IIS Searle Scholars Program Puget Sound Partners in Global Health Washington Research Foundation UW -Advanced Technology Initiative -TGIF BGI/U Alberta -Gane Wong -Jun Yu -Jun Wang -Andrew Mason -Lorne Tyrell BIOTEC/KMUTT Mahidol University - Prasit Palittapongarrnpim - Wasun Chantratita MSE -Mehmet Sarikaya -Candan Tamerler -et al. UW Microbiology -James Staley -John Mittler -Michael Lagunoff -Roger Bumgarner -Wesley Van Voorhis -et al. Collaborators: Budget: ~US$1 million/year total costs