PDF(Pubmed)
Abstract：
The development of open computational pipelines to accelerate the discovery of treatments for emerging diseases allows finding novel solutions in shorter periods of time. Consensus molecular docking is one of these approaches, and its main purpose is to increase the detection of real actives within virtual screening campaigns. Here we present dockECR, an open consensus docking and ranking protocol that implements the exponential consensus ranking method to prioritize molecular candidates. The protocol uses four open source molecular docking programs: AutoDock Vina, Smina, LeDock and rDock, to rank the molecules. In addition, we introduce a scoring strategy based on the average RMSD obtained from comparing the best poses from each single program to complement the consensus ranking with information about the predicted poses. The protocol was benchmarked using 15 relevant protein targets with known actives and decoys, and applied using the main protease of the SARS-CoV-2 virus. For the application, different crystal structures of the protease, and frames obtained from molecular dynamics simulations were used to dock a library of 79 molecules derived from previously co-crystallized fragments. The ranking obtained with dockECR was used to prioritize eight candidates, which were evaluated in terms of the interactions generated with key residues from the protease. The protocol can be implemented in any virtual screening campaign involving proteins as molecular targets. The dockECR code is publicly available at: https://github.com/rochoa85/dockECR.
摘要：
开发开放的计算管道以加速发现新兴疾病的治疗方法，可以在更短的时间内找到新的解决方案。共识分子对接是这些方法之一，其主要目的是在虚拟筛查活动中增加对真实活动的检测。这里我们介绍dockECR,一个开放的共识对接和排序协议，该协议实施指数共识排序方法来对分子候选物进行优先级排序。该协议使用四个开源分子对接程序：AutoDockVina，Smina,LeDock和rDock,对分子进行排序。此外,我们引入了一种基于平均RMSD的评分策略,该平均RMSD是通过比较每个程序的最佳姿势而获得的,以有关预测姿势的信息来补充共识排名.该方案是使用15种具有已知活性物质和诱饵的相关蛋白质靶标进行基准测试的，并使用SARS-CoV-2病毒的主要蛋白酶应用。对于应用程序，蛋白酶的不同晶体结构，和从分子动力学模拟获得的框架用于对接来自先前共结晶片段的79个分子的文库。使用dockECR获得的排名用于优先考虑8名候选人，根据与蛋白酶关键残基产生的相互作用进行评估。该方案可以在涉及蛋白质作为分子靶标的任何虚拟筛选活动中实施。dockECR代码可在以下网站公开获得：https://github.com/rochoa85/dockECR。
