Integration of virtual screening and experimental method to identify new Mpro of SARS-CoV-2 inhibitors.

COVID-19 is a global pandemic disease that has killed more than 6 million people. The main protease (Mpro), is a key component of the viral replication and a prime target for anti-COVID-19 drug discovery. In this context, several studies applying virtual screening discovered new Mpro inhibitors. In this work we selected the 10 best virtual hits from a virtual screening campaign and submitted them to 100 ns of molecular dynamics simulations. The most promising compound, taxifolin, and its structural analogue, quercetin, were selected for in vitro experimental evaluation against Mpro. Taxifolin and quercetin showed IC50 values of 870 µM and 50 µM, respectively. Mechanism of inhibition investigation indicated that the compounds are competitive inhibitors with the substrate, thereby suggesting that both ligands bind to the protein’s active site. These results indicate that computational approaches integrated with experimental methods are useful for the discovery of new enzyme inhibitors as anti-infective candidates.