INTERACTOMICS

RAM SAMUDRALAASSOCIATE PROFESSOR

UNIVERSITY OF WASHINGTON

NIH DIRECTOR’S PIONEER AWARD 2010

How does the genome of an organism specifyits behaviour and characteristics?

How can we use this information to improvehuman health and quality of life?

COMPUTATIONAL ANALYSIS OF NOVEL DRUG OPPORTUNITIESTHE CANDO TEAM

cando.compbio.washington.edu

GENOME SEQUENCE TO PROTEIN AND PROTEOME…STRUCTURE FUNCTION

SYSTEMS

INFRASTRUCTURE APPLICATIONS

EVOLUTION

THERAPEUTICS

NANOTECHNOLOGY

RICE

DESIGN

INTERACTION

COMPOUND

DNA/RNAPROTEIN

SHOTGUN DRUG REPURPOSINGALL KNOWN DRUGS (~5,000 FROM FDA)

ALL TARGETS WITH KNOWN STRUCTURE (~80,000+)

+

FRAGMENT BASEDDOCKING WITH DYNAMICS

(~120,000,000)

PRIORITISEDHITS

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 cariesHIV, HBRV, XMRV, rabies,encephalitis, cholera, tuberculosis, various cancers,and many more: cando.compbio.washington.edu

CLINICAL STUDIES/APPLICATION

INITIAL CLINICAL TRIALS

IN VITROSTUDIES

IN VIVO STUDIES

DISSOCIATION CONSTANTS (KD)(~300-500 + collaborations)

Multitarget protocol: 2,344 → 16 → 6 ≤ 1 µM ED50HTS protocol: 2,687 → 19 ≤ 1 µM ED50HTS protocol: 2,160 → 36 ≤ 1 µM ED50Docking protocol: 355,000 → 100 → 1 ≤ 10 µM ED50Docking protocol: 241,000 → 84 → 4 ≤ 10 µM ED50

14 targets MALARIA

Trends in Pharmacological Sciences, 2010.

DENGUE

PLoS Neglected Tropical Diseases, 2010.

2/4 ≤ µM ED50against dengue virus

Prediction #1Prediction #2

Viral E protein

PROSPECTIVE PRELIMINARY VERIFICATION

Observed:Function is inactivated.

KD protease ligand ≤ μMKD protease dimer ≤ μM

Experiment 1Experiment 2

HERPES(HSV, CMV, KSHV)

Predicted protease (dimer) + inhibitor:

He

rpe

s v

ira

l lo

ad

Lagunoff/ Van Voorhis/ Michael

NEISSERIA MENINGITIDISfactor 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, 2009.

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 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