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

Indeed, the analysis performed with Comulator software [32] shows that within viral Mpros evolutionary-correlated residues are dispersed throughout the structure. This indirectly supports our previous findings that distant amino acids mutation can contribute significantly to the binding site plasticity. It is worth adding that among evolutionary-correlated residues we identified also those that differ between SARS-CoV-2 and SARS-CoV Mpros, located on the C44-P52 loop ( Figure 6 ) and the F185-T201 linker loop. The CMA analysis indicates that particular residues in both loops are evolutionary-correlated. The Q189 from the linker loop correlates with residues from the C44-P52 loop, whereas R188, A191, and A194 correlate with selected residues from all domains, but not with the C44-P52 loop. As was shown, the mutation of amino acids distant from active site residues, that are evolutionary correlated, is most likely to modify the active site accessibility [33] . Figure 6 . Localisation of the evolutionary-correlated residues of Mpros (black sticks). The CMA analysis provided four groups of evolutionary-correlated residues. The SARS-CoV-2 Mpro structure is presented as cartoon, the active site residues are shown as red sticks, the unique residues of the SARS-CoV-2 Mpro as blue sticks, the asterisk (*) indicates the residue belonging to the evolutionary-correlated residues, unique for SARS-CoV Mpro. The loop C44-P52 is coloured black and the F185-T201 loop is orange. Please note, that within one of the correlated groups (upper left) the residues from C44-P52 loop are correlated with Q189 from the linker loop and with residue from III domain.