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

Additionally, the potential mutability of the binding cavity was investigated. Residues belonging to the binding cavity were found within 7 â„« from the N3 inhibitor. Then, we calculated the differences in the Gibbs free energy of protein folding with respect to the wild-type protein (Supplementary Table S3 ) and presented the results as a heat map. The most energetically favourable potential mutations are shown as green, neutral as white and unfavourable as red ( Figure 7B ). Interestingly, residues forming the catalytic dyad, namely H41 and C145, are also prone to mutate. However, probably the most important message comes from the analysis of the potential mutability of the C44-P52 loop. Mutation of four of them has a stabilising effect for the protein and for the rest the effect is near-neutral. These results indicate that the future evolution of the Mpro protein can significantly reduce the potential use of this protein as a molecular target for coronavirus treatment due to a highly probable development of drug resistance of this virus through mutations.