Stanley J. Watowich, Ph.D.

Publications (Pubmed)

Affiliations: Department of Biochemistry & Molecular Biology; Scientist, Sealy Center for Structural Biology & Molecular Biophysics
Tel: (409) 747-4749
Fax: (409) 747-4745
Route: 0645
623 Basic Science Building

Stanley J. Watowich, Ph.D.

June 1, 2017

Project wrap-up. We wish to thank the World Community Grid community for their support over these past years.

The World Community Grid phase of our "Discovering Dengue Drugs – Together" project completed its computations a while ago. As noted in a previous posting, we have been analyzing the results, retesting some of the calculations, modifying the underlying assumptions for the calculations, and testing compounds in the laboratory using in vitro and in vivo systems. We have worked with our medicinal chemists to synthesize variants of several initial inhibitor "hits" with the goal of improving their activity for planned pre-clinical trials. Our current designs, unfortunately, have not yet produced a highly potent dengue protease inhibitor suitable for in vivo testing. Thus, we are shifting our approach for this project and are now screening combinatorial chemistry libraries for protease inhibitor "hits" to use as starting points for "hit-to-lead" improvement. Free energy perturbation calculations and 3-D structure-guided design will be used to improve the potency and physiochemical properties of these hits.

The links below (pdf files)contain the ~1000 lowest scoring small molecules predicted to bind to the catalytic site of NS2B-NS3 proteases from dengue and West Nile viruses that were used in this virtual screening project. We hope this information may be of use to other investigators in their development of computational chemistry tools and/or dengue antivirals.

Dengue virus protease (PDB 2FOM) computational "hits"

West Nile virus protease (PDB 2FP7) computational "hits"

West Nile virus protease (PDB 2IJO)  computational "hits"