Discovering Dengue Drugs-Together

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Technical Details


Our drug discovery calculations will accurately predict binding free energies (a measure of howstrongly molecules interact) between small drug-like molecules and different flavivirus NS3 proteases. The binding binding free energy calculations combine the Autodock virtual docking program with rigorous mean field molecular dynamics algorithms (developed by Dr. Benoit Roux and his team at the University of Chicago).  Compounds predicted to bind tightly to each viral protease will be subsequently evaluated using in vitro biochemical and cell-based infectivity assays.

In Phase 1 of this project, AutoDock will fit over six million small molecules to each of the flavivirus NS3 proteases, so optimal binding orientations can be identified. AutoDock, developed by Dr. Arthur Olson of The Scripps Research Institute (San Diego, California, USA) and used in World Community Grid’s FightAIDS@Home project, can predict how small molecules might fit into a binding “pocket” on a protein of known atomic structure. These docking calculations will provide orientations for each small molecule-protease complex and a preliminary metric to discriminate between possible protease inhibitors and non-binding molecules.

In Phase 2 of this project, potential protease inhibitors predicted by Autodock will be organized into a concise database for detailed analysis with CHARMM, a molecular dynamics program developed by Professor Martin Karplus and his colleagues at Harvard University (Cambridge, Massachusetts, USA). Accurate CHARMM-based mean field binding free energy calculations will be applied to all potential protease inhibitors. The post-processing of the initial fitting results with binding free energy calculations will significantly reduce false-positive rates, thus speeding discovery of potent protease inhibitors.  Novel compounds predicted to be high-affinity inhibitors of flavivirus proteases will be tested in laboratory assays for antiviral activity.

Running these complex drug discovery calculations on World Community Grid will dramatically reduce the time required to complete this computationally intensive project. This will speed the discovery of compounds that inhibit dengue, hepatitis C, West Nile, and yellow fever virus replication.  This is a significant step towards developing new drugs to improve global health.

 

Overview of our drug discover method

Links to:

ZINC

Protein Data Bank

Autodock

CHARMM

Antechamber


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