New Protocol for Predicting the Ligand-Binding Site and Mode Based on the 3D-RISM/KH Theory
New Protocol for Predicting the Ligand-Binding Site and Mode Based on the 3D-RISM/KH Theory
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DOI：
10.1021/acs.jctc.9b01069
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发表时间：
2020-04-14
影响因子：
5.5
通讯作者：
Hirata，Fumio
中科院分区：
文献类型：
--
作者：
Sugita，Masatake;Hamano，Masataka;Hirata，Fumio
基于三维参考相互作用位点模型（3D-RISM）理论，利用Kovalenko-Hirata（KH）封闭关系，提出了一种快速确定蛋白质活性位点上小分子配体结合位置和模式的算法.研究的配体包括疏水性，酸性和碱性分子和两性离子。选择十八种不同类型的蛋白质作为这些配体的靶点，以检查算法的鲁棒性。称为“锚位点”的假想原子被定义在配体分子的几何中心处，其用作在平移和旋转空间中搜索配体分子的结合位置和模式的中心。基于蛋白质周围配体分子的SDF识别可能的结合位点（PBS），并根据SDF的峰高对PBS进行排序。基于z分数分析了50个PBS的SDF峰值的平均高度的偏差，z分数是对该站点的显著性的度量。在离晶体结构的锚位点最近的距离处发现的PBS被称为“最近位点”。通过改变欧拉角来探索配体分子在每个PBS处的取向，并且基于叠加近似来确定最可能的结合模式。配体分子的结合位置被成功预测为锚位点SDF中的不同峰之一，但有少数例外。基于叠加近似预测的配体分子的结合模式与9个系统的X射线晶体结构一致，占研究系统的一半。详细讨论了结果的意义。新协议的应用程序片段为基础的药物发现的建议。
An efficient algorithm to find the binding position and mode of small ligands bound at an active site of protein is proposed based on the spatial distribution function (SDF) obtained from the three-dimensional reference interaction site model (3D-RISM) theory with the Kovalenko–Hirata (KH) closure relation. The ligand examined includes hydrophobic, acidic, and basic molecules and zwitterions. Eighteen different types of proteins, which serve as targets for those ligands, are selected to examine the robustness of the algorithm. An imaginary atom, referred to as an “anchor site”, is defined at the center of geometry of a ligand molecule that serves as a center for searching the binding position and mode of the ligand molecule in the translational and rotational spaces. The probable binding sites (PBSs) are identified based on the SDFs of the ligand molecules around the protein, and the PBS is ranked according to the peak height of SDF. The deviations from the mean height of the peak values of SDFs for 50 PBSs are analyzed based on thez-score, which is a measure of prominence of the site. The PBS found at the closest distance from the anchor site of the crystal structure is referred to as the “nearest site”. The orientation of the ligand molecule at each PBS is explored by changing the Euler angles, and the most probable binding mode is determined based on the superposition approximation. The binding position of ligand molecules is successfully predicted as one of the distinct peaks in SDF of the anchor site, with a few exceptions. The binding mode of the ligand molecule predicted based on the superposition approximation is consistent with the X-ray crystal structure in nine systems, a half of the systems investigated. The significance of the results is discussed in detail. An application of the new protocol to fragment-based drug discovery is suggested.