In this update, Dr. Stan Watowich, principal investigator for the Discovering Dengue Drugs - Together project, explains how the research team is shifting their approach to data analysis. The research team has also released their best-scoring results in order to help other scientists conducting similar studies.
Screensaver for Discovering Dengue Drugs - Together
We wish to thank the World Community Grid volunteers 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. The mission of the project is to identify promising drug candidates to combat dengue, hepatitis C, West Nile, yellow fever, and other related viruses.
As noted in a previous update, 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 (test tube/culture dish) and in vivo (in living organisms) 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 contain the ~1000 lowest (best) 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)