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), Mpro. 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 Mpro, in a structural similarity study. The aim of this study was to determine the thirty most similar metabolites (10%) that may bind to the Mpro similar to GWS. Then, molecular docking against Mpro and pharmacophore studies led to the choice of five metabolites that exhibited good binding modes against the Mpro and good fit values against the generated pharmacophore model. Among them, three metabolites were chosen according to ADMET studies. The most promising Mpro 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.
Keywords: ADMET; DFT; MD simulations; SARS-CoV-2; docking; main protease; pharmacophoric; structural similarity.