Virtual Screening and Molecular Simulation Uncover Potent Traditional Chinese Medicine Small Molecules Against SARS-CoV-2 Mpro

Abstract

The binding pocket of the main protease (M^pro) is highly conserved and recognized as a promising target for designing anti-COVID-19 inhibitors. Given the significant role of traditional Chinese medicine in combating SARS-CoV-2, over 20,000 small molecules derived from traditional Chinese medicine were virtually screened against M^pro, resulting in the identification of TCM11135 (Hc1), TCM20595 (Hc2), TCM22179 (Hc3), and TCM22701 (Hc4) in the present study. Subsequent binding free energy calculations based on molecular dynamics simulations indicated that Hc1 and Hc4 exhibit favorable binding affinities for M^pro. By employing binding free energy decomposition and hydrogen bond analysis, this study uncovered the key residues in M^pro that contribute significantly to the binding energy or form hydrogen bonds with Hc1 and Hc4, thereby providing valuable insights for the optimization of these compounds. Additionally, the predicted ADME/T properties of Hc1 and Hc4 were found to be satisfactory, exhibiting favorable pharmacokinetic characteristics and no apparent toxicity. Therefore, Hc1 and Hc4 should be novel potent M^pro inhibitor lead compounds.