COVID-19 is a viral pandemic caused by SARS-CoV-2. Due to its highly contagious nature, millions of people are getting affected worldwide knocking down the delicate global socio-economic equilibrium. According to the World Health Organization, COVID-19 has affected over 186 million people with a mortality of around 4 million as of July 09, 2021. Currently, there are few therapeutic options available for COVID-19 control. The rapid mutations in SARS-CoV-2 genome and development of new virulent strains with increased infection and mortality among COVID-19 patients, there is a great need to discover more potential drugs for SARS-CoV-2 on a priority basis. One of the key viral enzymes responsible for the replication and maturation of SARS-CoV-2 is M^pro protein. In the current study, structure-based virtual screening was used to identify four potential ligands against SARS-CoV-2 M^pro from a set of 8,722 ASINEX library compounds. These four compounds were evaluated using ADME filter to check their ADME profile and druggability, and all the four compounds were found to be within the current pharmacological acceptable range. They were individually docked to SARS-CoV-2 M^pro protein to assess their molecular interactions. Further, molecular dynamics (MD) simulations was carried out on protein–ligand complex using Desmond at 100 ns to explore their binding conformational stability. Based on RMSD, RMSF and hydrogen bond interactions, it was found that the stability of protein–ligand complex was maintained throughout the entire 100 ns simulations for all the four compounds. Some of the key ligand amino acid residues participated in stabilizing the protein–ligand interactions includes GLN 189, SER 10, GLU 166, ASN 142 with PHE 66 and TRP 132 of SARS-CoV-2 M^pro. Further optimization of these compounds could lead to promising drug candidates for SARS-CoV-2 M^pro target.

COVID-19 是由 SARS-CoV-2 引起的病毒性大流行。由于其高度传染性，全世界数百万人受到影响，破坏了微妙的全球社会经济平衡。根据世界卫生组织的数据，截至 2021 年 7 月 9 日，COVID-19 已影响超过 1.86 亿人，死亡率约为 400 万。目前，可用于控制 COVID-19 的治疗选择很少。随着 SARS-CoV-2 基因组的快速突变和新毒株的出现，COVID-19 患者感染率和死亡率增加，迫切需要优先发现更多潜在的 SARS-CoV-2 药物。负责 SARS-CoV-2 复制和成熟的关键病毒酶之一是 M ^pro蛋白质。在目前的研究中，基于结构的虚拟筛选用于从一组 8,722 个 ASINEX 库化合物中识别出四种针对 SARS-CoV-2 M ^{pro的潜在配体。}使用 ADME 过滤器对这四种化合物进行了评估，以检查它们的 ADME 谱和成药性，发现所有四种化合物都在当前药理学可接受的范围内。它们分别与 SARS-CoV-2 M ^pro对接蛋白质来评估它们的分子相互作用。此外，使用 Desmond 在 100 ns 对蛋白质-配体复合物进行分子动力学 (MD) 模拟，以探索它们的结合构象稳定性。基于 RMSD、RMSF 和氢键相互作用，发现蛋白质-配体复合物的稳定性在所有四种化合物的整个 100 ns 模拟中都保持不变。参与稳定蛋白质-配体相互作用的一些关键配体氨基酸残基包括 SARS-CoV-2 M ^pro的 GLN 189、SER 10、GLU 166、ASN 142 和 PHE 66 和 TRP 132 。这些化合物的进一步优化可能会为 SARS-CoV-2 M ^pro靶标带来有希望的候选药物。