Effects of Water Placement on Predictions of Binding Affinities for p38 alpha MAP Kinase Inhibitors

James Luccarelli, Julien Michel, Julian Tirado-Rives, William L. Jorgensen

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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 p38 alpha MAP kinase. Overall correlation with experimental data 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.

Original languageEnglish
Pages (from-to)3850-3856
Number of pages7
JournalJournal of Chemical Theory and Computation
Issue number12
Publication statusPublished - Dec 2010

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