A Multistage In Silico Study of Natural Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Among a group of 310 natural antiviral natural metabolites, our team identified three compounds as the most potent natural inhibitors against the SARS-CoV-2 main protease (PDB ID: 5R84), M^pro. The identified compounds are sattazolin and caprolactin A and B. A validated multistage in silico study was conducted using several techniques. First, the molecular structures of the selected metabolites were compared with that of GWS, the co-crystallized ligand of M^pro, in a structural similarity study. The aim of this study was to determine the thirty most similar metabolites (10%) that may bind to the M^pro similar to GWS. Then, molecular docking against M^pro and pharmacophore studies led to the choice of five metabolites that exhibited good binding modes against the M^pro and good fit values against the generated pharmacophore model. Among them, three metabolites were chosen according to ADMET studies. The most promising M^pro inhibitor was determined by toxicity and DFT studies to be caprolactin A (292). Finally, molecular dynamics (MD) simulation studies were performed for caprolactin A to confirm the obtained results and understand the thermodynamic characteristics of the binding. It is hoped that the accomplished results could represent a positive step in the battle against COVID-19 through further in vitro and in vivo studies on the selected compounds.