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

A close inspection of the binding site cavity provides further details of cosolvent distribution. The benzene hot-spots for the SARS-CoV-2 Mpro structure are localised deep inside the active site cavity, while SARS-CoV Mpro features mostly benzene hot-spots at the cavity entrance ( Figure 5 ). This is interesting since, in the absence of cosolvent molecules, the water accessible volume for SARS-CoV-2 Mpro was 50% smaller than in the case of SARS-CoV Mpro, underlining huge plasticity of the binding cavity and suggesting large conformational changes induced by interaction with a potential ligand. It is also interesting, that both global and local hot-spots of the SARS-CoV Mpro structure are located in the proximity of the C44-P52 loop, which potentially regulates the access to the active site. Figure 5 . Localisation of the local hot-spots identified in the binding site cavities in SARS-CoV-2 and SARS-CoV main proteases. Hot-spots of individual cosolvents are represented by spheres, and their size reflects the hot-spots density. The colour coding is as follows: purple -urea, green -dimethylsulfoxide, yellowmethanol, orange -acetonitrile, pink -phenol, red -benzene. The active site residues are shown as red sticks, and the proteins' structures are shown in cartoon representation, loop 44-52 is grey.