Molecular Dynamics Simulations Indicate the SARS-CoV-2 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design

Maria Bzówka; Karolina Mitusinska; Agata Raczynska; Aleksandra Samol; Jack Tuszynski; Artur Góra

In this paper, we reported on molecular dynamics simulations of the main protease (Mpro), whose crystal structures have been released. We compared the Mpro for SARS-CoV-2 with a highly similar SARS-CoV protein. In spite of a high level of sequence similarity between these two homologous proteins, their active sites show major differences in both shape and size indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, a detailed analysis of the binding pocket's conformational changes during simulation time indicates its flexibility and plasticity, which dashes hope for rapid and reliable drug design. Moreover, our findings show the presence of a flexible loop regulating the access to the binding site pocket. A successful inhibitor may need to have an ability to relocate the loop from the entrance to bind to the catalytic pocket. However, mutations leading to changes in the amino acid sequence of the loop, while not affecting the folding of the protein, may result in the putative inhibitors' inability to access the binding pocket and provide a probable development of drug resistance. To avoid that situation that the future evolution of the Mpros can wipe out all our efforts, we should focus on key functional residues or those whose further mutation will destabilise the protein.