Allosteric Modulation of the Main Protease (M(Pro)) of SARS-CoV-2 by Casticin—Insights from Molecular Dynamics Simulations

Inhibition of the main protease (M(pro)) of SARS-CoV-2 has been suggested to be vital in shutting down viral replication in a host. Most efforts aimed at inhibiting M(Pro) activity have been channeled into competitive inhibition at the active site, but this strategy will require a high inhibitor concentration and impressive inhibitor-M(Pro) binding affinity. Allosteric inhibition can potentially serve as an effective strategy for alleviating these limitations. In this study, the ability of antiviral natural products to inhibit M(Pro) in an allosteric fashion was explored with in silico techniques. Molecular docking revealed a strong interaction between casticin, an antiviral flavonoid, and M(pro) at a site distant from the active site. This site, characterized as a distal site, has been shown to have an interdependent dynamic effect with the active site region. M(pro) only, M(pro)-peptide (binary) and M(pro)-peptide-casticin (ternary) complexes were subjected to molecular dynamics simulations for 50 ns to investigate the modulatory activity of casticin binding on M(pro). Molecular dynamic simulations revealed that binding of casticin at the distal site interferes with the proper orientation of the peptide substrate in the oxyanion hole of the active site, and this could lead to a halt or decrease in catalytic activity. This study therefore highlights casticin as a potential allosteric modulator of the SARS-CoV-2 main protease, which could be optimized and developed into a potential lead compound for anti-SARS-CoV-2 chemotherapy. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42250-022-00411-7.