Effects of Water Placement on Predictions of Binding Affinities for p38α MAP Kinase Inhibitors
- 23 November 2010
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Chemical Theory and Computation
- Vol. 6 (12), 3850-3856
- https://doi.org/10.1021/ct100504h
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 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.Keywords
This publication has 30 references indexed in Scilit:
- Rigorous Free Energy Calculations in Structure‐Based Drug DesignMolecular Informatics, 2010
- Prediction of protein–ligand binding affinity by free energy simulations: assumptions, pitfalls and expectationsJournal of Computer-Aided Molecular Design, 2010
- Energetics of Displacing Water Molecules from Protein Binding Sites: Consequences for Ligand OptimizationJournal of the American Chemical Society, 2009
- Efficient Drug Lead Discovery and OptimizationAccounts of Chemical Research, 2009
- The Thermodynamics of Protein–Ligand Interaction and Solvation: Insights for Ligand DesignJournal of Molecular Biology, 2008
- Computation of binding free energy with molecular dynamics and grand canonical Monte Carlo simulationsThe Journal of Chemical Physics, 2008
- Calculating Free Energy Differences Using Perturbation TheoryPublished by Springer Science and Business Media LLC ,2007
- Understanding Noncovalent Interactions: Ligand Binding Energy and Catalytic Efficiency from Ligand‐Induced Reductions in Motion within Receptors and EnzymesAngewandte Chemie-International Edition, 2004
- Analysis of Binding Affinities for Celecoxib Analogues with COX-1 and COX-2 from Combined Docking and Monte Carlo Simulations and Insight into the COX-2/COX-1 SelectivityJournal of the American Chemical Society, 2000
- Computational Alchemy To Calculate Absolute Protein−Ligand Binding Free EnergyJournal of the American Chemical Society, 1998