Molecular docking, dynamics, and quantum chemical study of vanillylacetone and beta-hydroxy ketone derivatives against M<sub>pro</sup> of SARS-CoV-2

Abstract

This study is carried out to find novel active drug candidates which can effectively bind to key residues of main protease (Mpro) of SARSCoV-2. We performed molecular docking of fifty-seven (57) ligands from two classes: vanillylacetone and its derivatives and beta-hydroxy ketone derivatives against  Mpro of SARS-CoV-2. We also docked three antiviral drugs as reference/benchmark drugs including remdesivir (RDV), chloroquine (CQ), and  hydroxychloroquine (HCQ) against Mpro for comparison of inhibition tendencies of selected ligands. Binding energies of our reference drugs are as: CQ =  −5.1 kcal mol⁻¹ (with predicted inhibition constant (K_{i pred}) = 177 µmol), HCQ = −5.7 kcal mol⁻¹ (K_{i pred} = 64.07 µmol) and RDV −6.3 kcal mol⁻¹ (K_{i pred}  = 13.95 µmol). We got remarkable results for our docked ligands as 79% of total ligands indicated binding energies better than CQ, 39 % better than  both HCQ and CQ, and 19 % better than all reference drugs. More interestingly interaction analysis of eight best-docked ligands showed that they  interacted with desired key residues of M_pro. We further selected the four best-docked ligands L1 = −6.6 kcal mol⁻¹ (K_{i pred} =13.95 µmol), L6 = −7.0 kcal  mol⁻¹ (K_{i pred} = 7.08 µmol), L34 = −6.0 kcal mol⁻¹ (K_{i pred} = 38.54 µmol), and L₅₀ = −6.6 kcal mol⁻¹ (K_{i pred} =13.95 µmol) for further analysis by quantum  chemical study, molecular dynamic (MD) simulations and ADMET analysis. We have also carried out MD-simulations of six more docked ligand  L2, L14, L20, L36, L46 and L48 some of which were showing weak binding affinities and some average binding affinities to check their simulation  behavior. Their RMSD, RMSF and binding free energy results were also quite satisfying. We believe the current investigation will evoke the scientific  community and highlights the potential of selected compounds for potential use as antiviral compounds against Mpro of SARS-CoV-2.