WCG Discovering Dengue Drugs – Together

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Alez
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#1 WCG Discovering Dengue Drugs – Together

Post by Alez »

Discovering Dengue Drugs – Together


Phase 1 of Discovering Dengue Drugs – Together has ended (August, 2009). The scientists for this project are anaylzing the results to prepare for Phase 2 of the project.

Project Status and Findings:
Information about this project is provided on the web pages below and by the project scientists on the Discovering Dengue Drugs - Together website.
For the latest status report, please go to the Discovering Dengue Drugs - Together status report .
If you have comments or questions about this project, please visit the Discovering Dengue Drugs – Together forum.
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Mission
The mission of Discovering Dengue Drugs – Together is to identify promising drug leads to combat the Dengue, Hepatitis C, West Nile, Yellow Fever, and other related viruses. The extensive computing power of World Community Grid will be used to complete the structure-based drug discovery calculations required to identify these leads.

Significance
This project will discover promising drug leads that stop the replication of viruses within the Flaviviridae family. Members of this family, including dengue, hepatitis C, West Nile, and Yellow fever viruses, pose significant health threats throughout the developed and developing world. More than 40% of the world's population is at risk for infection by dengue virus. Annually, 1.5 million people are treated for dengue fever and dengue hemorrhagic fever. Hepatitis C virus has infected ~2% of the world's population. Yellow fever and West Nile viruses have also had significant global impact. Unfortunately, there are no drugs that effectively treat these diseases. Consequently, the supportive care necessary to treat these infections and minimize mortality severely strains already burdened health facilities throughout the world. The discovery of both broad–spectrum and specific antiviral drugs is expected to significantly improve global health.

Approach
One promising approach to combat these viruses and prevent them from causing disease is to develop drugs that inhibit the viral NS3 protease. The NS3 protease is an enzyme critical for virus replication, and its amino acid sequence and atomic structure are very similar among the different disease–causing flaviviruses. Since the atomic structure of the NS3 protease is known, we can utilize advanced structure–based computational drug discovery methods to identify small molecule protease inhibitors.

Dr. Stan Watowich and his research team at The University of Texas Medical Branch (Galveston, Texas, USA) have made significant progress in this direction, having discovered compounds that inhibit dengue and West Nile virus proteases and prevent virus replication in cell culture. However, additional drug candidates need to be discovered to improve the likelihood of converting drug leads into approved drugs for treating flavivirus infections.
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#2 Re: WCG Discovering Dengue Drugs – Together

Post by Alez »

Project news can be found here
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Alez
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#3 Re: WCG Discovering Dengue Drugs – Together

Post by Alez »

Latest report Discovering Dengue Drugs - Together Takes a New Approach to Data Analysis

Discovering Dengue Drugs - Together Takes a New Approach to Data Analysis
By: Dr. Stan Watowich, PhD
University of Texas Medical Branch (UTMB) in Galveston, Texas
18 Oct 2017

Summary
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)

West Nile virus protease (PDB 2FP7)

West Nile virus protease (PDB 2IJO)
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