药效团
机制(生物学)
化学
计算生物学
蛋白酶
分子动力学
严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)
2019年冠状病毒病(COVID-19)
生物化学
酶
生物
医学
计算化学
物理
病理
传染病(医学专业)
疾病
量子力学
作者
Danyang Xiong,Xiaoyu Zhao,Song Luo,John Z. H. Zhang,Lili Duan
标识
DOI:10.1021/acs.jpclett.2c02428
摘要
Convenient and efficient therapeutic agents are urgently needed to block the continued spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, the mechanism for the novel orally targeted SARS-CoV-2 main protease (Mpro) inhibitor S-217622 is revealed through a molecular dynamics simulation. The difference in the movement modes of the S-217622-Mpro complex and apo-Mpro suggested S-217622 could inhibit the motility intensity of Mpro, thus maintaining their stable binding. Subsequent energy calculations showed that the P2 pharmacophore possessed the highest energy contribution among the three pharmacophores of S-217622. Additionally, hot-spot residues H41, M165, C145, E166, and H163 have strong interactions with S-217622. To further investigate the resistance of S-217622 to six mainstream variants, the binding modes of S-217622 with these variants were elucidated. The subtle differences in energy compared to that of the wild type implied that the binding patterns of these systems were similar, and S-217622 still inhibited these variants. We hope this work will provide theoretical insights for optimizing novel targeted Mpro drugs.
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