The Discovery of Potential SARS-CoV-2 Natural Inhibitors among 4924 African Metabolites Targeting the Papain-like Protease: A Multi-Phase In Silico Approach.

Four compounds, hippacine, 4,2'-dihydroxy-4'-methoxychalcone, 2',5'-dihydroxy-4-methoxychalcone, and wighteone, were selected from 4924 African natural metabolites as potential inhibitors against SARS-CoV-2 papain-like protease (PLpro, PDB ID: 3E9S). A multi-phased in silico approach was employed to select the most similar metabolites to the co-crystallized ligand ( TTT ) of the PLpro through molecular fingerprints and structural similarity studies. Followingly, to examine the binding of the selected metabolites with the PLpro (molecular docking. Further, to confirm this binding through molecular dynamics simulations. Finally, in silico ADMET and toxicity studies were carried out to prefer the most convenient compounds and their drug-likeness. The obtained results could be a weapon in the battle against COVID-19 via more in vitro and in vivo studies.