Microbial Natural Products as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro)

Abstract

The main protease (M^pro) of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings using a library of microbial natural products (>24,000 compounds). Subsequent filtering of the resulted hits according to the Lipinski's rules was applied to select only the drug-like molecules. Top-scoring hits were further filtered out depending on their ability to show constant good binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme's conformers. Final MDS experiments were performed on the ligand-protein complexes (compounds <b>1</b><b>-</b><b>12,</b> Table S1) to verify their binding modes and calculate their binding free energy. Consequently, a final selection of six compounds (<b>1</b><b>-</b><b>6</b>) was proposed to possess high potential as anti-SARS-CoV-2 drug candidates. Our study provides insight into the role of the M^pro structural flexibility during interactions with the possible inhibitors and sheds light on the structure-based design of anti-coronavirus disease 2019 (COVID-19) therapeutics targeting SARS-CoV-2.