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 total of 2 µs classical molecular dynamics (cMD) simulations of both SARS-CoV-2 and SARS-CoV Mpros with different starting points were run to examine the plasticity of their binding cavities. A combination of the cMD approach with water molecules used as molecular probes is assumed to provide a highly detailed picture of the protein's interior dynamics [29] . The small molecules tracking approach was used to determine the accessibility of the active site pocket in both SARS-CoV and SARS-CoV-2 Mpros, and a local distribution approach was used to provide information about an overall distribution of solvent in the proteins' interior. To properly examine the flexibility of both active site cavities, we used the time-window mode implemented in AQUA-DUCT software [30] to analyse the water molecules' flow through the cavity in a 10 ns time step and combined that with the outer pocket calculations to examine the plasticity and maximal accessible volume (MAV) of the binding cavity.