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Research: Discovering Dengue Drugs - Together - Phase 2: Project Overview
 
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Discovering Dengue Drugs - Together
- Phase 2


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. If you have comments or questions about this project, please visit the Discovering Dengue Drugs - Together Phase 2 forum.

Mission
The mission of Discovering Dengue Drugs - Together - Phase 2 is to identify promising drug candidates 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 drug candidates.

Significance
This project will discover promising drug candidates 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 also have 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, researchers can utilize advanced structure-based computational drug discovery methods to identify small molecule protease inhibitors.

Researchers 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 and to minimize viral resistance. To succeed in this effort, researchers are using the computational power of World Community Grid to complete a novel two-phased project in computer-based drug discovery.

Phase 1 (completed August 2009) of the "Discovering Dengue Drugs - Together" project used the program AutoDock (developed by Dr. A. Olson and his team at The Scripps Research Institute) to systematically screen ~3 million small "drug-like" molecules and identify several thousand molecules that might interact strongly with the virus NS3 protease. These calculations predicted the likely structure of each small molecule when bound to a protease, and provided a preliminary metric to discriminate between possible protease inhibitors (termed Phase 1 "hits") and non-binding molecules.

Unfortunately, it is common for ~90-95% of Phase 1 hits to be false positives. Thus, it is very inefficient to test Phase 1 hits in the laboratory (although University of Texas Medical Branch [UTMB] researchers have found several Phase 1 compounds that showed good activity in biochemical and cell-based assays).

Phase 2 of the project is designed to reduce the number of Phase 1 false positive (i.e., dead end) predictions. Phase 2 will use the program CHARMM (developed by Martin Karplus and his team at Harvard) to take several thousand promising Phase 1 hits and run each hit through computationally demanding molecular dynamics simulations to accurately calculate Gibbs free energy of binding. These calculations will better predict how tightly small drug-like molecules bind to the different flavivirus proteases. This will remove many of the false positives from the Phase 1 hit list. Thus, Phase 2 will produce a hit list that is significantly enriched in true positives. Testing Phase 2 hits in UTMB laboratories will be much more productive, efficient, and rewarding than testing Phase 1 hits.

Notice of workunit availability
The nature of the Phase 2 free energy calculations and research requires each protease-ligand system to execute three sequential programs, with manual analysis and intervention required between each program. Moreover, each program has very different processing characteristics and computing environment requirements. As the project switches between programs, Phase 2 workunits may be temporarily unavailable and the project will appear to run intermittently. This is in contrast to most World Community Grid projects, where workunits are continuously available until a project ends. It is suggested that World Community Grid members allow other Grid projects to run whenever Phase 2 workunits are not available.

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