Mechanistic insight into sars‐cov‐2 mpro inhibition by organoselenides: The ebselen case study

The main protease (Mpro) of SARS‐CoV‐2 is a current target for the inhibition of viral replication. Through a combined Docking and Density Functional Theory (DFT) approach, we investigated in‐silico the molecular mechanism by which ebselen (IUPAC: 2‐phenyl‐1,2‐ benzoselenazol‐3‐one), the most famous and pharmacologically active organoselenide, inhibits Mpro. For the first time, we report on a mechanistic investigation in an enzyme for the formation of the covalent ‐S‐Se‐ bond between ebselen and a key enzymatic cysteine. The results highlight the strengths and weaknesses of ebselen and provide hints for a rational drug design of bioorganic selenium‐based inhibitors.