3CL-蛋白酶似乎是开发抗SARS-CoV-2药物的非常有希望的药物靶标。解析结构的可用性允许进行基于结构的计算方法,即使缺乏已知的抑制剂阻止了对所执行模拟的正确验证。该研究的创新思想是利用已知的SARS-CoV3CL-Pro抑制剂作为训练集来执行和验证多个虚拟筛查活动。使用四个不同的程序进行对接模拟(Fred,滑翔,LiGen,和植物)进行了研究多种结合模式(通过结合空间)和多种异构体/状态(通过发展相应的异构空间)的作用。计算出的对接分数用于开发共识模型,这允许对所产生的性能进行深入比较。平均而言,所达到的性能表明,四个对接引擎之间对异构差异和多种结合模式的敏感性不同。详细来说,Glide和LiGen是最能从异构和结合空间中获益的工具,分别,而弗雷德是最不敏感的程序。所获得的结果强调了组合各种对接工具以优化预测性能的卓有成效的作用。一起来看,所执行的模拟允许合理开发高性能虚拟筛查工作流程,可以通过考虑不同的3CL-Pro结构进一步优化,更重要的是,通过包括真正的SARS-CoV-23CL-Pro抑制剂(作为学习集)。
The 3CL-Protease appears to be a very promising medicinal target to develop anti-SARS-CoV-2 agents. The availability of resolved structures allows structure-based computational approaches to be carried out even though the lack of known inhibitors prevents a proper validation of the performed simulations. The innovative idea of the study is to exploit known inhibitors of SARS-CoV 3CL-Pro as a training set to perform and validate multiple virtual screening campaigns. Docking simulations using four different programs (Fred, Glide, LiGen, and PLANTS) were performed investigating the role of both multiple binding modes (by binding space) and multiple isomers/states (by developing the corresponding isomeric space). The computed docking scores were used to develop
consensus models, which allow an in-depth comparison of the resulting performances. On average, the reached performances revealed the different sensitivity to isomeric differences and multiple binding modes between the four docking engines. In detail, Glide and LiGen are the tools that best benefit from isomeric and binding space, respectively, while Fred is the most insensitive program. The obtained results emphasize the fruitful role of combining various docking tools to optimize the predictive performances. Taken together, the performed simulations allowed the rational development of highly performing virtual screening workflows, which could be further optimized by considering different 3CL-Pro structures and, more importantly, by including true SARS-CoV-2 3CL-Pro inhibitors (as learning set) when available.