|
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.
|
