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

Danyang Xiong, Xiaoyu Zhao, Song Luo, John Z.H. Zhang, Lili Duan

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8893-8901
Number of pages9
JournalJournal of Physical Chemistry Letters
Volume13
Issue number38
DOIs
StatePublished - Sep 29 2022

ASJC Scopus subject areas

  • Materials Science(all)
  • Physical and Theoretical Chemistry

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