Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia.
Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia.
J Biomol Struct Dyn. 2022;40(19):9347-9360. doi: 10.1080/07391102.2021.1927845. Epub 2021 May 21.
The SARS-CoV-2 3CL protease (3CLpro) shows a high similarity with 3CL proteases of other beta-coronaviruses, such as SARS and MERS. It is the main enzyme involved in generating various non-structural proteins that are important for viral replication and is one of the most important proteins responsible for SARS-CoV-2 virulence. In this study, we have conducted an ensemble docking of molecules from the DrugBank database using both the crystallographic structure of the SARS-CoV-2 3CLpro, as well as five conformations obtained after performing a cluster analysis of a 300 ns molecular dynamics (MD) simulation. This procedure elucidated the inappropriateness of the active site for non-covalent inhibitors, but it has also shown that there exists an additional, more favorable, allosteric binding site, which could be a better target for non-covalent inhibitors, as it could prevent dimerization and activation of SARS-CoV-2 3CLpro. Two such examples are radotinib and nilotinib, tyrosine kinase inhibitors already in use for treatment of leukemia and which binding to the newly found allosteric binding site was also confirmed using MD simulations. Communicated by Ramaswamy H. Sarma.
SARS-CoV-2 的 3CL 蛋白酶（3CLpro）与其他β冠状病毒（如 SARS 和 MERS）的 3CL 蛋白酶具有高度相似性。它是产生各种非结构蛋白的主要酶，这些蛋白对病毒复制至关重要，是导致 SARS-CoV-2 毒力的最重要的蛋白之一。在这项研究中，我们使用 SARS-CoV-2 3CLpro 的晶体结构以及对 300ns 分子动力学（MD）模拟进行聚类分析后获得的五个构象，对 DrugBank 数据库中的分子进行了组合对接。该程序阐明了活性位点不适合非共价抑制剂，但也表明存在一个额外的、更有利的别构结合位点，它可能是更好的非共价抑制剂靶点，因为它可以防止 SARS-CoV-2 3CLpro 的二聚化和激活。这方面的两个例子是 radotinib 和 nilotinib，它们是已经用于治疗白血病的酪氨酸激酶抑制剂，通过 MD 模拟也证实了它们与新发现的别构结合位点的结合。由 Ramaswamy H. Sarma 传达。
