title: 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.
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107.
authors.forename: James
authors.initials: J
authors.lastname: Luccarelli
authors.forename: Julien
authors.initials: J
authors.lastname: Michel
authors.forename: Julian
authors.initials: J
authors.lastname: Tirado-Rives
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen