In silico Exploration of Inhibition Mechanism of Lianhua Qingwen Formula (LQF) Interaction on SARS-CoV-2 Mpro

It is well known that the severe epidemic respiratory disease COVID-19 was caused by the novel coronavirus SARS-CoV-2. Lianhua Qingwen Formula (LQF), as a traditional Chinese medicine (TCM) formula, exerts anti-coronavirus activity by suppressing viral replication and activating anti-inflammatory effects. In this work, the unknown molecular inhibition mechanism of LQF ingredients on the main protease (Mpro) of SARS-CoV-2 was investigated. From the screening of pharmacophore model, docking, molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations, it is found that Isoliquiritin apioside, Liquiritin apioside, Forsythoside E, Rutin, and Isoliquiritin possess much larger binding free energies than reference X77. These five hit molecules are characterized by multi-hydroxyl groups, which facilitate the formation of hydrogen bonds with polar amino acid residues at S1’ subsite and rationalize their primary binding to Mpro with electrostatic rather than usual van der Waals (vdW) interaction. In addition, the Isoliquiritin apioside, Liquiritin apioside, and Rutin were also identified as potential inhibitors on SARS-CoV Mpro, possessing much larger binding free energies with large electrostatic interaction than that of reference ENB. The present study can not only enrich the scaffolds of Mpro of SARS-CoV family inhibitors, but also provide an idea for the new drug development.