The recent pandemic outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), raised global health and economic concerns. Phylogenetically, SARS-CoV-2 is closely related to SARS-CoV, and both encode the enzyme main protease (M^pro/3CL^pro), which can be a potential target inhibiting viral replication. Through this work, we have compiled the structural aspects of M^pro conformational changes, with molecular modeling and 1-μs MD simulations. Long-scale MD simulation resolves the mechanism role of crucial amino acids involved in protein stability, followed by ensemble docking which provides potential compounds from the Traditional Chinese Medicine (TCM) database. These lead compounds directly interact with active site residues (His41, Gly143, and Cys145) of M^pro, which plays a crucial role in the enzymatic activity. Through the binding mode analysis in the S1, S1′, S2, and S4 binding subsites, screened compounds may be functional for the distortion of the oxyanion hole in the reaction mechanism, and it may lead to the inhibition of M^pro in SARS-CoV-2. The hit compounds are naturally occurring compounds; they provide a sustainable and readily available option for medical treatment in humans infected by SARS-CoV-2. Henceforth, extensive analysis through molecular modeling approaches explained that the proposed molecules might be promising SARS-CoV-2 inhibitors for the inhibition of COVID-19, subjected to experimental validation.

最近由严重的急性呼吸系统综合症冠状病毒2（SARS-CoV-2）引起的大流行COVID-19爆发引起了全球健康和经济关注。在系统发育上，SARS-CoV-2与SARS-CoV密切相关，并且都编码酶主蛋白酶（M ^pro / 3CL ^pro），该酶可能是抑制病毒复制的潜在靶标。通过这项工作，我们整理了M ^pro的结构方面通过分子建模和1-μsMD模拟来改变构象。远程MD模拟解决了关键氨基酸与蛋白质稳定性有关的机理作用，然后进行整体对接，从传统中药（TCM）数据库中提供潜在化合物。这些先导化合物直接与M ^pro的活性位点残基（His41，Gly143和Cys145）相互作用，后者在酶活性中起关键作用。通过S1，S1'，S2和S4结合亚位点的结合模式分析，筛选出的化合物可能会对反应机理中氧阴离子孔的变形起作用，并可能导致M ^pro的抑制在SARS-CoV-2中。命中化合物是天然存在的化合物。它们为感染SARS-CoV-2的人类提供了可持续且容易获得的医疗选择。此后，通过分子建模方法进行的广泛分析解释说，经过实验验证，提出的分子可能是有希望的SARS-CoV-2抑制剂，可抑制COVID-19。