Molecular dynamics and absolute binding free energy studies of piperine derivatives as potential inhibitors of SARS-CoV-2 main protease

Abstract

The work presents a library of piperine derivatives as potential inhibitors of the main protease protein (Mpro) functionality using Docking Studies, Molecular Dynamics (MD) Simulations and Absolute Binding Free-Energy calculations. 342 ligands were selected for this work and docked with Mpro protein. Among all the ligands studied, PIPC270, PIPC299, PIPC252, PIPC63, PIPC311 were the top five docked conformations having significant hydrogen bonding and hydrophobic interactions inside the active pocket of Mpro. These top five ligands were subjected to MD simulations for 100 ns using GROMACS. Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA) and hydrogen bond analysis revealed that the ligands bounded to protein remain stable without significant deviations during the course of MD simulations. Absolute binding free energy (ΔGb) was calculated for theses complexes and found that the ligand PIPC299 shows the prevalent binding affinity with binding free-energy of about −113.05 Kcal/mol. Thus, these molecules can be further tested by in vitro and in vivo studies on Mpro. This study lays a path to explore the new functionality of piperine derivatives as novel drug like molecules.Communicated by Ramaswamy H. Sarma