The pivotal role of β‐lactone stereochemistry in the development of <scp>SARS</scp> ‐ <scp>CoV</scp> ‐2 M ^pro inhibitors

Abstract From the arrival of the SARS‐CoV‐2 coronavirus in 2019 and its associated COVID‐19 pandemic, worldwide efforts have been focused on developing a drug to treat patients. The SARS‐CoV‐2 main protease (Mpro) is one of the main targets for drug design due to its key role in the virus replication and its distinguished ability to cleave peptides after a glutamine residue. Inspired by the knowledge of the inhibition mechanism of 20S Proteasome, this work focuses on exploring the inhibition process of SARS‐CoV‐2 M pro with a β‐lactone, as well as the impact of the stereochemistry of this compound on the stability of the enzyme:inhibitor binding formation complex. Based on molecular dynamics simulations with classical and hybrid QM/MM potentials, the free energy landscape of the mechanism of the formation of the covalent complex has been computed. The results show how one of the stereoisomers of the β‐lactone derivative forms a stable reactant non‐covalent complex in the active site of M pro . Analysis of the kinetics and thermodynamics of the inhibition process suggests that this non‐peptidyl compound can be considered a lead compound for future developments of efficient therapeutic compounds to treat patients with COVID‐19.