Evaluation of SARS-CoV-2 main protease and inhibitor interactions using dihedral angle distributions and radial distribution function

Abstract

In order to evaluate the interactions between a potential drug candidate like inhibitor N3 and the residues in substrate binding site of SARS-CoV-2 main protease (Mpro), we used molecular docking and dynamics simulations. The structural features describing the degrees of folding states of Mpro formed by beta-barrels and alpha-helices were analyzed by means of root mean square deviation, root mean square fluctuation, radius of gyration, residue velocity, H-bonding, dihedral angle distributions and radial distribution function. All of the residues forming ligand binding domain (LBD) of Mpro lie within the allowed region of the dihedral angle distributions as observed from the equilibrating best pose of Mpro-N3 system. Sharp peaks of radial distribution function (RDF) for H-bonding atom pairs (about 2 Å radial distance apart) describe the strong interactions between inhibitor and SARS-CoV-2 Mpro. During MD simulations, HSE163 has the lowest residue speed offering a sharp RDF peak whereas GLN192 has the highest residue speed resulting a flat RDF peak for the H-bonding atom pairs of Mpro-N3 system. Along with negative values of coulombic and Lenard-Jones energies, MM/PBSA free energy of binding contributed by the non-covalent interactions between Mpro and N3 has been obtained to be -19.45 ± 3.6 kcal/mol. These physical parameters demonstrate the binding nature of an inhibitor in Mpro-LBD. This study will be helpful in evaluating the drug candidates which are expected to inhibit the SARS-CoV-2 structural proteins.