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 general, all the above-mentioned findings indicate potential difficulties in the identification of specific inhibitors toward Mpro proteins. First, the binding site itself is characterised by huge plasticity and probably even distant to active site mutations modify Mpro binding properties. Secondly, the C44-P52 loop regulates access to the active site and can contribute to the discrimination of potential inhibitors. Therefore, additional mutations in the above-mentioned regions, which could appear during further SARS-CoV-2 evolution, can significantly change the affinity between Mpro and its ligands. To verify potential threat of further mutability of the Mpro protein we performed: i) correlated mutation analysis (CMA) on multiple sequence alignment, ii) the analysis of the contribution of already identified differences between the SARS-CoV and SARS-CoV-2 Mpros to protein stability, and iii) prediction of further possible mutations caused by the most probable mutations, the substitution of single nucleotides in the mRNA sequence of Mpro.