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

The analysis of the water hot-spots shows that the catalytic water hot-spot dominates water distribution inside the binding cavity. The remaining water hot-spots correspond to a much lower water density level and are on the borders of the binding cavity, which suggests a rather hydrophobic or neutral interior of the binding cavity. The MixMD simulations performed with various cosolvents have further confirmed these observations. The largest number and the densest hot-spots were located within the binding cavity and the region essential for Mpros dimerisation [31] , between the II and III domains. The deep insight into the local hot-spots distribution of the various cosolvents underlines the large differences in binding sites plasticity. The smaller binding cavity of the SARS-CoV-2 enlarged significantly in the presence of a highly hydrophobic cosolvent. The benzene hot-spots were detected deep inside the cavity, and also near the C44-P52 loop. In contrast, in the case of the SARS-CoV, benzene hot-spots were located only in the vicinity of the C44-P52 loop. Such a conclusion may also imply that a sufficiently potent inhibitor of SARS-CoV and/or SARS-CoV-2 Mpros needs to be able to open its way to the active site before it can successfully bind to its cavity. These results support the regulatory role of the C44-P52 loop and again alert against unwarranted use of simplified approaches for drug repositioning or docking.