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Accelerating the drug discovery process requires predictive computational protocols capable of reducing or simplifying the synthetic and/or combinatorial challenge. Docking-based virtual screening methods have been developed and successfully applied to a number of pharmaceutical targets. In this review, we first present the current status of docking and(More)
The results of cognate docking with the prepared Astex dataset provided by the organizers of the "Docking and Scoring: A Review of Docking Programs" session at the 241st ACS national meeting are presented. The MOE software with the newly developed GBVI/WSA dG scoring function is used throughout the study. For 80 % of the Astex targets, the MOE docker(More)
We report the development and validation of a novel suite of programs, FITTED 1.0, for the docking of flexible ligands into flexible proteins. This docking tool is unique in that it can deal with both the flexibility of macromolecules (side chains and main chains) and the presence of bridging water molecules while treating protein/ligand complexes as(More)
Several modifications and additions to Fitted1.5 led to the development of Fitted2.6. Among the novel implementations are a matching algorithm-enhanced genetic algorithm and a ring conformational search algorithm. With these various optimizations, we also hoped to remove the biases and to develop a docking program that would provide results (i.e., poses) as(More)
Local ordering of water in the first hydration shell around a solute is different from isotropic bulk water. This leads to effects that are captured by explicit solvation models and missed by continuum solvation models which replace the explicit waters with a continuous medium. In this paper, we introduce the First-Shell Hydration (FiSH) model as a first(More)
Golgi alpha-mannosidase II (GMII), a zinc-dependent glycosyl hydrolase, is a promising target for drug development in anti-tumor therapies. Using X-ray crystallography, we have determined the structure of Drosophila melanogaster GMII (dGMII) complexed with three different inhibitors exhibiting IC50's ranging from 80 to 1000 microM. These structures, along(More)
HCV NS5B polymerase is a validated target for the treatment of hepatitis C, known to be one of the most challenging enzymes for docking programs. In order to improve the low accuracy of existing docking methods observed with this challenging enzyme, we have significantly modified and updated F itted 1.0, a recently reported docking program, into F itted(More)
Two structural models have been developed to explain how agonist binding leads to ionotropic glutamate receptor (iGluR) activation. At alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) iGluRs, full and partial agonists close the agonist-binding domain (ABD) to different degrees whereas agonist-induced domain closure is apparently fixed at(More)
As part of a large medicinal chemistry program, we wish to develop novel selective estrogen receptor modulators (SERMs) as potential breast cancer treatments using a combination of experimental and computational approaches. However, one of the remaining difficulties nowadays is to fully integrate computational (i.e., virtual, theoretical) and medicinal(More)