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 mixed-solvent MD simulations were run with 6 cosolvents: acetonitrile (ACN), benzene (BNZ), dimethylsulfoxide (DMSO), methanol (MEO), phenol (PHN), and urea (URE). Cosolvents were used as specific molecular probes, representing different chemical properties and functional groups that would complement the different regions of the binding site and the protein itself. Using small molecules tracking approach we analysed the flow through the Mpros structures and identified the regions in which those molecules are being trapped and/or caged, located within the protein itself (global hot-spots; Figure 4 , Supplementary Figure S2 ) and inside the binding cavity (local hot-spots; Figure 5 , Supplementary Figure S3 ). The size and location of both types of hot-spots differ and provide complementary information. The global hot-spots identify potential binding/interacting sites in the whole protein structure and additionally provide . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.27.968008 doi: bioRxiv preprint information about regions attracting particular types of molecules, whereas local hot-spots describe the actual available binding space of a specific cavity. Figure S2 ). The largest number and the densest hot-spots are located within the binding cavity and the region essential for Mpros dimerisation [31] , between the II and III domains. The binding cavity is particularly occupied by urea, benzene and phenol hot-spots, which is especially interesting, since these solvents exhibit different chemical properties.