Institute for Computational Molecular Science, and Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States.
Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.
J Chem Inf Model. 2021 Sep 27;61(9):4745-4757. doi: 10.1021/acs.jcim.1c00684. Epub 2021 Aug 17.
The main protease of SARS-CoV-2 virus, M, is an essential element for viral replication, and inhibitors targeting M are currently being investigated in many drug development programs as a possible treatment for COVID-19. An pilot screen of a highly focused collection of compounds was initiated to identify new lead scaffolds for M. These efforts identified a number of hits. The most effective of these was compound SIMR-2418 having an inhibitory IC value of 20.7 μM. Molecular modeling studies were performed to understand the binding characteristics of the identified compounds. The presence of a cyclohexenone warhead group facilitated covalent binding with the Cys residue of M. Our results highlight the challenges of targeting M protease and pave the way toward the discovery of potent lead molecules.
新型冠状病毒 2 型（SARS-CoV-2）病毒的主要蛋白酶 M 是病毒复制的必要元素，目前许多药物研发项目都在针对 M 开发抑制剂，以期用于治疗 COVID-19。本研究启动了对高度集中的化合物库的先导筛选，以确定 M 的新型先导骨架。这些努力发现了许多命中化合物。其中最有效的是化合物 SIMR-2418，其抑制 IC 值为 20.7 μM。进行了分子建模研究以了解鉴定化合物的结合特征。环己烯酮弹头基团的存在促进了与 M 的 Cys 残基的共价结合。我们的结果强调了靶向 M 蛋白酶的挑战，并为发现有效的先导分子铺平了道路。
