DOCKTITE-A Highly Versatile Step-by-Step Workflow for Covalent Docking and Virtual Screening in the Molecular Operating Environment
DOCKTITE-A Highly Versatile Step-by-Step Workflow for Covalent Docking and Virtual Screening in the Molecular Operating Environment
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DOI：
10.1021/ci500681r
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发表时间：
2015-02-01
影响因子：
5.6
通讯作者：
Schmidt, Boris
中科院分区：
文献类型：
--
作者：
Scholz, Christoph;Knorr, Sabine;Schmidt, Boris
与靶标形成共价键对于许多成功的药物至关重要，但对弹头或受体类别没有重大限制的共价对接工具很少见，而且使用有限。在这项工作中，我们介绍了 DOCKTITE，这是一种在分子操作环境 (MOE) 中进行共价对接的高度通用的工作流程，结合了自动弹头筛选、亲核侧链连接、基于药效基团的对接和新颖的共识评分方法。综合验证研究包括 35 种蛋白质/配体复合物的姿势预测，其平均 RMSD 为 1.74 埃，预测率为 71.4%（RMSD 低于 2 埃）、虚拟筛选，受试者工作特征 (ROC) 的曲线下面积 (AUC) 为 0.81，预测结合亲和力与实验结合亲和力之间存在显着相关性 (rho = 0.806， R-2 = 0.649，p < 0.005）。
The formation of a covalent bond with the target is essential for a number of successful drugs, yet tools for covalent docking without significant restrictions regarding warhead or receptor classes are rare and limited in use. In this work we present DOCKTITE, a highly versatile workflow for covalent docking in the Molecular Operating Environment (MOE) combining automated warhead screening, nucleophilic side chain attachment, pharmacophore-based docking, and a novel consensus scoring approach. The comprehensive validation study includes pose predictions of 35 protein/ligand complexes which resulted in a mean RMSD of 1.74 angstrom and a prediction rate of 71.4% with an RMSD below 2 angstrom, a virtual screening with an area under the curve (AUC) for the receiver operating characteristics (ROC) of 0.81, and a significant correlation between predicted and experimental binding affinities (rho = 0.806, R-2 = 0.649, p < 0.005).