Docking Covalent Inhibitors: A Parameter Free Approach To Pose Prediction and Scoring
Docking Covalent Inhibitors: A Parameter Free Approach To Pose Prediction and Scoring
复制标题
DOI：
10.1021/ci500118s
复制
发表时间：
2014-07-01
影响因子：
5.6
通讯作者：
Harder, Edward
中科院分区：
文献类型：
--
作者：
Zhu, Kai;Bonelli, Kenneth W.;Harder, Edward
虽然许多流行的对接程序包括一个设施，以考虑共价配体，大规模的系统对接验证研究共价抑制剂已经稀疏。在本文中，我们介绍了它的发展和。验证了一种新的方法对接和评分共价抑制剂，其中包括传统的非共价对接，共价连接点的启发式形成，和蛋白质配体复合物的结构优化。这种方法结合了对接程序Glide和蛋白质结构建模程序Prime的优势，并且不需要任何参数拟合来研究其他共价反应类型。我们首先通过预测38个共价结合复合物的天然结合几何形状来测试这种方法。预测姿态的平均RMSD为1.52埃，并且7696个测试集抑制剂具有小于2.0埃的RMSD。此外，本文构建的表观亲和力分数在虚拟筛选研究和两个不同系列的同类化合物的SAR性质的表征上进行测试，取得了令人满意的成功。
Although many popular docking programs include a facility to account for covalent ligands, large-scale systematic docking validation studies of covalent inhibitors have been sparse. In this paper, we present the development and. validation of a novel approach for docking and scoring covalent inhibitors, which consists of conventional noncovalent docking, heuristic formation of the covalent attachment point, and structural refinement of the protein ligand complex. This approach combines the strengths of the docking program Glide and the protein structure modeling program Prime and does not require any parameter fitting for the study of additional covalent reaction types. We first test this method by predicting the native binding geometry of 38 covalently bound complexes. The average RMSD of the predicted poses is 1.52 angstrom, and 7696 of test set inhibitors have an RMSD of less than 2.0 angstrom. In addition, the apparent affinity score constructed herein is tested on a virtual screening study and the characterization of the SAR properties of two different series of congeneric compounds with satisfactory success.