Molecular Mechanism of the Non-Covalent Orally Targeted SARS-CoV-2 Mpro Inhibitor S-217622 and Computational Assessment of Its Effectiveness against Mainstream Variants

Authors：Xiong, Danyang; Zhao, Xiaoyu; Luo, Song; Zhang, John Z. H.^*; Duan, Lili^*

Source：Journal of Physical Chemistry Letters, 2022.

DOI：10.1021/acs.jpclett.2c02428

• FREE-ENERGY
• DYNAMICS
• RECEPTOR
• BINDING
• SUBSTRATE
• PROTEIN
• SPIKE

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 (M-pro) inhibitor S-217622 is revealed through a molecular dynamics simulation. The difference in the movement modes of the S-217622-M-pro complex and apo-M-pro suggested S-217622 could inhibit the motility intensity of M-pro, 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 M-pro drugs.

• Institution
  中国科学院