The pivotal role of β-lactone stereochemistry in the development of SARS-CoV-2 Mpro inhibitors.

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 Mpro 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 Mpro. 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.