Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel corona virus that causes corona virus disease 2019 (COVID-19). The COVID-19 rapidly spread across the nations with high mortality rate even as very little is known to contain the virus at present. In the current study, we report novel natural metabolites namely, ursolic acid, carvacrol and oleanolic acid as the potential inhibitors against main protease (M^pro) of COVID-19 by using integrated molecular modeling approaches. From a combination of molecular docking and molecular dynamic (MD) simulations, we found three ligands bound to protease during 50 ns of MD simulations. Furthermore, the molecular mechanic/generalized/Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations showed that these chemical molecules have stable and favourable energies causing strong binding with binding site of M^pro protein. All these three molecules, namely, ursolic acid, carvacrol and oleanolic acid, have passed the ADME (Absorption, Distribution, Metabolism, and Excretion) property as well as Lipinski's rule of five. The study provides a basic foundation and suggests that the three phytochemicals, viz. ursolic acid, carvacrol and oleanolic acid could serve as potential inhibitors in regulating the M^pro protein's function and controlling viral replication. Communicated by Ramaswamy H. Sarma.

Keywords: COVID-19; carvacrol; oleanolic acid; protease; ursolic acid.

Figure 1.

Flowchart of pipeline used in present study to identify the phytochemical based inhibitors of M^pro.

Figure 2.

Schematic representation of molecular docking between M^pro and phytochemicals; (a) 3D structure of coronavirus derived from the RCSB-Protein Data Bank (PDB); (b) crystal structure of main protease of COVID-19 obtained from the PDB with PDB ID:5R7Y (c)interaction between M^pro and oleanolic acid with −6.0 kcal/mol docking energy; (d) interaction between M^pro and carvacrol with docking energy −4.0 kcal/mol; (e) interaction between M^pro and ursolic acid with −5.9 kcal/mol docking energy. Interactions were visualized using maestro and discovery studio programs.

Figure 3

RMSD analysis of protein backbone during MD simulation.

Figure 4.

Analysis of RMSD of ligands and M^pro complexes; M^pro-carvacrol complex (Black), M^pro-oleanolic acid complex (Red), M^pro-ursolic acid complex (Blue).

Figure 5.

Analysis of RMSF of Cα during MD simulation; M^pro-carvacrol complex (Black), M^pro-oleanolic acid complex (Red), M^pro-ursolic acid complex (Blue).

Figure 6.

Intermolecular hydrogen bonds between the ligands and M^pro protein; M^pro-carvacrol complex (Black), M^pro-oleanolic acid complex (Red), M^pro-ursolic acid complex (Blue).

Figure 7.

(a) Radius of gyration (Rg); M^pro-carvacrol complex (Black), M^pro-oleanolic acid complex (Blue), M^pro-ursolic acid complex (Red); (b) Solvent surface accessible area (SASA); M^pro-carvacrol complex (Black), M^pro-oleanolic acid complex (Red), M^pro-ursolic acid complex (Blue).