Effects of Water Placement on Predictions of Binding Affinities for p38α MAP Kinase Inhibitors
Effects of Water Placement on Predictions of Binding Affinities for p38α MAP Kinase Inhibitors
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DOI：
10.1021/ct100504h
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发表时间：
2010-12-01
影响因子：
5.5
通讯作者：
Jorgensen, William L.
中科院分区：
文献类型：
--
作者：
Luccarelli, James;Michel, Julien;Jorgensen, William L.
应用Monte Carlo自由能微扰（MC/FEP）方法计算了17种P38 α MAP激酶抑制剂的相对结合亲和力。当使用带有储存溶剂盒的传统程序水合复合物时，发现与实验数据的总体相关性较小。当MC/FEP的计算重复使用初始溶剂分布优化的水的位置算法JAWS时，获得了显着的改善精度。结果强调了水分子在配体结合位点的准确位置的重要性，为可靠的预测结合的相对自由能。
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.