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Effects of Water Placement on Predictions of Binding Affinities for p38α MAP Kinase Inhibitors
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Current address: Institute of Structural and Molecular Biology, The University of Edinburgh, Edinburgh, EH9 3JR, U.K.
Section: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.
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This article has been cited by 4 ACS Journal articles (4 most recent appear below).
Molecular Dynamics Simulation and Free Energy Calculation Studies of the Binding Mechanism of Allosteric Inhibitors with p38α MAP Kinase
Ying Yang, Yulin Shen, Huanxiang Liu, and Xiaojun YaoJournal of Chemical Information and Modeling2011 51 (12), 3235-3246Molecular Dynamics Simulation and Free Energy Calculation Studies of the Binding Mechanism of Allosteric Inhibitors with p38α MAP Kinase
Ying Yang, Yulin Shen, Huanxiang Liu, and Xiaojun YaoJournal of Chemical Information and Modeling2011 51 (12), 3235-3246p38 MAP kinase is a promising target for anti-inflammatory treatment. The classical kinase inhibitors imatinib and sorafenib as well as BI-1 and BIRB-796 were reported to bind in the DFG-out form of human p38α, known as type II or allosteric kinase ...
A GRID-Derived Water Network Stabilizes Molecular Dynamics Computer Simulations of a Protease
Hannes G. Wallnoefer, Klaus R. Liedl, and Thomas FoxJournal of Chemical Information and Modeling2011 51 (11), 2860-2867A GRID-Derived Water Network Stabilizes Molecular Dynamics Computer Simulations of a Protease
Hannes G. Wallnoefer, Klaus R. Liedl, and Thomas FoxJournal of Chemical Information and Modeling2011 51 (11), 2860-2867Structural water molecules are crucial for the stability and function of proteins. Recently, we presented a molecular dynamics (MD) study on blood coagulation factor Xa (fXa) to investigate the effect of water molecules on the flexibility of the protein ...
A Direct Comparison of the MM-GB/SA Scoring Procedure and Free-Energy Perturbation Calculations Using Carbonic Anhydrase as a Test Case: Strengths and Pitfalls of Each Approach
Cristiano R. W. GuimarãesJournal of Chemical Theory and Computation2011 7 (7), 2296-2306A Direct Comparison of the MM-GB/SA Scoring Procedure and Free-Energy Perturbation Calculations Using Carbonic Anhydrase as a Test Case: Strengths and Pitfalls of Each Approach
Cristiano R. W. GuimarãesJournal of Chemical Theory and Computation2011 7 (7), 2296-2306MM-GB/SA scoring and free energy perturbation (FEP) calculations have emerged as reliable methodologies to understand structural and energetic relationships to binding. In spite of successful applications to elucidate the structure–activity relationships ...
Polarizable Water Networks in Ligand–Metalloprotein Recognition. Impact on the Relative Complexation Energies of Zn-Dependent Phosphomannose Isomerase with d-Mannose 6-Phosphate Surrogates
Nohad Gresh, Benoit de Courcy, Jean-Philip Piquemal, Johanna Foret, Stéphanie Courtiol-Legourd, and Laurent SalmonThe Journal of Physical Chemistry B2011 115 (25), 8304-8316Polarizable Water Networks in Ligand–Metalloprotein Recognition. Impact on the Relative Complexation Energies of Zn-Dependent Phosphomannose Isomerase with d-Mannose 6-Phosphate Surrogates
Nohad Gresh, Benoit de Courcy, Jean-Philip Piquemal, Johanna Foret, Stéphanie Courtiol-Legourd, and Laurent SalmonThe Journal of Physical Chemistry B2011 115 (25), 8304-8316Using polarizable molecular mechanics, a recent study [de Courcy et al. J. Am. Chem. Soc., 2010, 132, 3312] has compared the relative energy balances of five competing inhibitors of the FAK kinase. It showed that the inclusion of structural water ...
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- Published In Issue December 14, 2010
- Article ASAPNovember 23, 2010
- Received: September 3, 2010
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