Transcript Document

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…
STRUCTURE
FUNCTION
INTERACTION
PROTEIN
DNA/RNA
COMPOUND
SYSTEMS
INFRASTRUCTURE
APPLICATIONS
RICE
THERAPEUTICS
NANOTECHNOLOGY
DESIGN
EVOLUTION
SHOTGUN DRUG REPURPOSING
ALL KNOWN DRUGS
FRAGMENT BASED
(~5,000 FROM FDA) DOCKING WITH DYNAMICS
(~120,000,000)
PRIORITISED
HITS
DISSOCIATION CONSTANTS (KD)
(~300-500 + collaborations)
+
ALL TARGETS WITH KNOWN
STRUCTURE (~80,000+)
MACHINE
LEARNING
IN VITRO
STUDIES
herpes, malaria, dengue
hepatitis C, dental caries
CLINICAL STUDIES/APPLICATION
HIV, HBRV, XMRV, rabies,
encephalitis, cholera,
tuberculosis, various cancers,
and many more: cando.compbio.washington.edu
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
INITIAL CLINICAL TRIALS
IN VIVO STUDIES
PROSPECTIVE PRELIMINARY VERIFICATION
Predicted
protease (dimer) +
inhibitor:
HERPES
DENGUE
(HSV, CMV, KSHV)
Viral E protein
Observed:
Function is inactivated.
Prediction #1
Prediction #2
KD protease ligand ≤ μM
KD protease dimer ≤ μM
Herpes viral load
Experiment 1
Experiment 2
2/4 ≤ µM ED50
against dengue virus
PLoS Neglected Tropical Diseases, 2010.
14 targets
MALARIA
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
Trends in Pharmacological Sciences, 2010.
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
Homo sapiens
factor H
Neisseria meningitidis
factor H binding protein
Topamax
Schneider et al. Nature, 2009.
Voacamine
Treatement of epilepsy
Anti malarial agent
Loop movement breaks the interface
Chopra/White
ACKNOWLEDGEMENTS
Current group members: Past group members:
•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
•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
•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
Collaborators:
Funding agencies:
•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.
•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
Budget:
• ~US$1 million/year total costs