Effects of Water Placement on Predictions of Binding Affinities for p38α MAP Kinase Inhibitors.

ABSTRACT: Monte Carlo free energy perturbation (MC/FEP) calculations have been applied to compute the relative binding affinities of 17 congeneric pyridazo-pyrimidinone inhibitors of the protein p38α MAP kinase. Overall correlation with experiment was found to be modest when the complexes were hydrated using a traditional procedure with a stored solvent box. Significant improvements in accuracy were obtained when the MC/FEP calculations were repeated using initial solvent distributions optimized by the water placement algorithm JAWS. The results underscore the importance of accurate placement of water molecules in a ligand binding site for the reliable prediction of relative free energies of binding.

SUBMITTER: Luccarelli J 

PROVIDER: S-EPMC3029023 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature