Virtual Screening and Molecular Simulation Uncover Potent Traditional Chinese Medicine Small Molecules Against SARS‐CoV‐2 M ^pro

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.