We will create a comprehensive computational drug discovery platform by enhancing a novel technique for a dynamic, fragment based, screening of small molecule compounds against the three dimensional structures of multiple protein targets from infectious disease causing pathogens, followed by prospective in vitro and in vivo experimental verification. We will further modify the most promising lead candidates computationally and screen them against all known human proteins and variants simultaneously to assess for side effects against essential proteins, and to ensure that they possess safe and effective absorption, distribution, metabolism, and excretion profiles against major proteins in known drug delivery pathways. The top ranking leads will again be experimentally verified, and the computational protocol will be itera- tively refined using machine learning techniques. We will initially focus on discovering preclinical drug candidates against infections caused by all eight human herpes viruses (HHVs). This virus family infects billions of humans worldwide every year and is the source of significant mortality in immunocompromised patients. Broad spectrum therapeutics against these key pathogens will benefit the entire global community. In contrast to other computational efforts, my group has successfuly applied and experimentally verified their predictions of inhibitors to treat herpes, malaria, and dengue. This was accomplished at a fraction of the time, effort, and cost typically required by pharmaceutical companies. Our significant successes thus far attest to the efficacy of our drug discovery technologies. The Pioneer Award funds will therefore allow us to bridge the gap of discovering computationally predicted lead compounds and demonstrating their preclinical effectiveness for further clinical and therapeutic use. The ultimate goal is to create a comprehensive computational drug discovery pipeline, applicable to any disease, thereby increasing the suc

Agency
National Institute of Health (NIH)
Institute
National Library of Medicine (NLM)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1LM011509-04
Application #
8509784
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (01))
Program Officer
Ye, Jane
Project Start
2010-09-30
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$797,049
Indirect Cost
$316,899
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Minie, Mark; Chopra, Gaurav; Sethi, Geetika et al. (2014) CANDO and the infinite drug discovery frontier. Drug Discov Today 19:1353-63
Hung, Ling-Hong; Samudrala, Ram (2014) fast_protein_cluster: parallel and optimized clustering of large-scale protein modeling data. Bioinformatics 30:1774-6
Afzal, Ahmed J; Srour, Ali; Goil, Abhishek et al. (2013) Homo-dimerization and ligand binding by the leucine-rich repeat domain at RHG1/RFS2 underlying resistance to two soybean pathogens. BMC Plant Biol 13:43