Murphy Robert B, Repasky Matthew P, Greenwood Jeremy R, Tubert-Brohman Ivan, Jerome Steven, Annabhimoju Ramakrishna, Boyles Nicholas A, Schmitz Christopher D, Abel Robert, Farid Ramy, Friesner Richard A
Schrödinger, Inc. , 101 SW Main Street, Portland Oregon 97204, United States.
Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
J Med Chem. 2016 May 12;59(9):4364-84. doi: 10.1021/acs.jmedchem.6b00131. Epub 2016 Apr 22.
We have developed a new methodology for protein-ligand docking and scoring, WScore, incorporating a flexible description of explicit water molecules. The locations and thermodynamics of the waters are derived from a WaterMap molecular dynamics simulation. The water structure is employed to provide an atomic level description of ligand and protein desolvation. WScore also contains a detailed model for localized ligand and protein strain energy and integrates an MM-GBSA scoring component with these terms to assess delocalized strain of the complex. Ensemble docking is used to take into account induced fit effects on the receptor conformation, and protein reorganization free energies are assigned via fitting to experimental data. The performance of the method is evaluated for pose prediction, rank ordering of self-docked complexes, and enrichment in virtual screening, using a large data set of PDB complexes and compared with the Glide SP and Glide XP models; significant improvements are obtained.
我们开发了一种用于蛋白质 - 配体对接和评分的新方法WScore，该方法纳入了对明确水分子的灵活描述。水的位置和热力学性质源自WaterMap分子动力学模拟。水结构用于提供配体和蛋白质去溶剂化的原子水平描述。WScore还包含一个用于局部配体和蛋白质应变能的详细模型，并将MM - GBSA评分组件与这些项相结合，以评估复合物的离域应变。采用整体对接来考虑受体构象的诱导契合效应，并通过拟合实验数据来分配蛋白质重组自由能。使用大量PDB复合物数据集对该方法在姿势预测、自对接复合物的排名排序以及虚拟筛选中的富集情况进行了评估，并与Glide SP和Glide XP模型进行了比较；结果获得了显著改进。
