Discovering Dengue Drugs-Together

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Project Status


Current Project Report

 

Distribution of Hepatitis C, Dengue, and West Nile around the world.

 

Watowich Lab

 

 June 3, 2008 update

·        Our Discovering Dengue Drugs – Together project has currently benefited from >6,000 years of computer processing time on World Community Grid. We are extremely grateful and indebted to those individuals who have unselfishly volunteered their computers to help us search for cures to dengue, West Nile, and Hepatitis C diseases.

·        Trypsin protease (Protein Data Bank entry 1EB2) has been screened against our 2.2 million member ligand library to provide a negative control for inhibitor discovery (termed workgroup 0401).

·        Hepatitis C virus protease was used as a target to screen a combined drug and lead-like library containing 2.2 million compounds. These calculations (termed workgroup 0501) were completed in ~ 2 months.

·        A second optimization of the Autodock program and its parameters was completed in late April 2008. This included modifying the code to enable multiple ligands to be combined into a single workunit for delivery to end-user computers. Although this increased the execution time for each workunit, this has decreased network traffic on the World Community Grid servers and enabled more ligands for the DiscoveringDengueDrugs-Together project to be distributed. This has allowed our workflow to increase by ~2- to 3-fold.

·        Recoding and porting the CHARM molecular dynamics program for use on World Community Grid is underway. The CHARMM program will be the main software for Phase 2 of this project. It will enable us to accurately calculate free energies of binding for tens of thousands of the best fit protease-ligand structures determined in the Phase 1 Autodock calculations. These calculations are necessary to correct false-positive energy predictions made by the Autodock scoring function.

·         A variant of the dengue virus NS3 protease was used as a target to screen a combined drug and lead-like library containing 2.2 million compounds. These calculations (termed workgroup 0202) were completed in <1 month.

·        A variant of the West Nile virus NS3 protease was used as a target to screen a combined drug and lead-like library containing 2.2 million compounds. These calculations (termed workgroup 0302) were completed in <1 month.

·        We are preparing to launch a new version of the Phase 1 Autodock software that contains error checking embedded within each workunit. This will eliminate the use of duplicate (or triplicate) calculations to validate each workunit. This improved code should allow us to reach our goal of screening our ligand library against a single protein in less than 2 weeks.

·        The combined results from screening our ligand library against the dengue virus NS3 protease and a dengue protease variant are being analyzed in our laboratory to identify common hits (i.e., compounds predicted to fit into the protease active site). These results will be filtered to remove inhibitors predicted to bind trypsin, since broad inhibitors may have adverse human effects. Compounds with promising inhibition constants and specific dengue protease binding will be synthesized and evaluated in cell culture and animal models.

·        The combined results from screening our ligand library against West Nile and dengue proteases are being analyzed in our laboratory to identify potential flavivirus protease inhibitors. These results will be filtered to remove compounds predicted to bind trypsin, since broad-spectrum protease inhibitors may have adverse human effects. Compounds with promising inhibition constants and specific flavivirus protease binding will be synthesized and evaluated in cell culture and animal models.

 

 

 

 

Past Project Reports

 January 22, 2008 update

·        An initial optimization of docking parameters was completed in early Fall, 2007. This allowed us to reduce computation time ~20-fold without impacting the accuracy of pose predications.

·        Dengue virus NS3 protease (Protein Data Bank entry 2FOM) was used as a target to screen a combined drug and lead-like library containing 2.2 million compounds. These calculations (termed workgroup 0201) were completed in ~2 months. Grid resources for these calculations were limited to <10% of World Community Grid to minimize file transfer bottlenecks resulting from packing only a single ligand into each workunit.

·        Predicted inhibitors obtained from screening our ligand library against dengue virus NS3 protease are being analyzed in our laboratory using a protease inhibition assay. Compounds with promising inhibition constants will be further evaluated in cell culture and animal models.

·        West Nile virus NS3 protease (Protein Data Bank entry 2FP7) was used as a target to screen a combined drug and lead-like library containing 2.2 million compounds. These calculations (termed workgroup 0301) were completed in ~2 months and ended in early January ‘08. Grid resources for these calculations were also limited to <10% of World Community Grid to minimize file transfer bottlenecks resulting from packing only a single ligand into each workunit.

·        Predicted inhibitors obtained from screening our ligand library against West Nile virus NS3 protease are being analyzed in our laboratory using a protease inhibition assay. Compounds with promising inhibition constants will be further evaluated in cell culture and animal models.

·        Additional docking calculation optimizations are entering beta testing. These optimizations will enable us to reach our goal of screening our ligand library against a single protein in less than 2 weeks. This involves packaging multiple ligands (~10) into a single workunit, thereby minimizing file transfer bottlenecks. In addition, checksum error checking will be embedded within each workunit, eliminating the use of redundant calculations to validate each workunit.

·        Trypsin protease (Protein Data Bank entry 1EB2) is being screened against our ligand library to provide a negative control for inhibitor discovery (termed workgroup 0401).

·        Hepatitis C virus protease is being readied for computational screening.

·        Our Discovering Dengue Drugs – Together project has currently benefited from 3,626 years of computer processing time on World Community Grid. We are grateful to those individuals who have unselfishly volunteered their computers to help us find cures for dengue, West Nile, and Hepatitis C diseases.

August 21, 2007 update

·        Phase 1 (Autodock) of this project was launched August 21, 2007.

 

 

 

 


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