Exploring the Therapeutic Potential of Petiveria alliacea L. Phytochemicals: A Computational Study on Inhibiting SARS-CoV-2's Main Protease (Mpro)

Abstract

The outbreak of SARS-CoV-2, also known as the COVID-19 pandemic, is still a critical risk factor for both human life and the global economy. Although, several promising therapies have been introduced in the literature to inhibit SARS-CoV-2, most of them are synthetic drugs that may have some adverse effects on the human body. Therefore, the main objective of this study was to carry out an in-silico investigation into the medicinal properties of Petiveria alliacea L. (P. alliacea L.)-mediated phytocompounds for the treatment of SARS-CoV-2 infections since phytochemicals have fewer adverse effects compared to synthetic drugs. To explore potential phytocompounds from P. alliacea L. as candidate drug molecules, we selected the infection-causing main protease (Mpro) of SARS-CoV-2 as the receptor protein. The molecular docking analysis of these receptor proteins with the different phytocompounds of P. alliacea L. was performed using AutoDock Vina. Then, we selected the three top-ranked phytocompounds (myricitrin, engeletin, and astilbin) as the candidate drug molecules based on their highest binding affinity scores of -8.9, -8.7 and -8.3 (Kcal/mol), respectively. Then, a 100 ns molecular dynamics (MD) simulation study was performed for their complexes with Mpro using YASARA software, computed RMSD, RMSF, PCA, DCCM, MM/PBSA, and free energy landscape (FEL), and found their almost stable binding performance. In addition, biological activity, ADME/T, DFT, and drug-likeness analyses exhibited the suitable pharmacokinetics properties of the selected phytocompounds. Therefore, the results of this study might be a useful resource for formulating a safe treatment plan for SARS-CoV-2 infections after experimental validation in wet-lab and clinical trials.

Keywords: SARS-CoV-2 infections; computational approaches; main protease; phytocompound; toxicity.

Figure 1

Graphical representation of the current research.

Figure 2

The 3D conformational view of the target protein Mpro (PDB ID: 6LU7) from SARS-CoV-2 virus, colored by amino acid type. Such as, Red: Hydrophobic, Green: Polar, Blue: Positively charged, Magenta: Negatively charged.

Figure 3

Display of post-docking analysis and ligand–protein interactions: (A) myricitrin vs. Mpro, (B) engeletin vs. Mpro, and (C) astilbin vs. Mpro.

Figure 4

Molecular docking representation of the three top-ranked phytochemicals with other independent proteins of SARS-CoV-2.

Figure 5

(a) Graphical presentation of the RMSD of the backbone atoms (C, Cα, and N) for each docked complex, and (b) the RMSF evaluated from the average RMSF of the atoms constituting the residue.

Figure 6

Representation of the Rg plot showing the changes observed in the conformational behavior of the all protein–ligand complex of aastilbin–Mpro, engeletin–Mpro, and myricitrin–Mpro.

Figure 7

Representation of the SASA study for the selected complex structure of astilbin–Mpro, engeletin–Mpro (red), and myricitrin–Mpro (green).

Figure 8

MM-PBSA binding energy calculation of myricitrin (green), engeletin (red) and astilbin (black) bound with Mpro calculated from the MD simulation trajectory.

Figure 9

Ca-residue cross-correlation profiles for the myricitrin complex (A), engeletin complex (B), and astilbin complex (C).

Figure 10

Graphical representation of the PCA analysis of the top-ranked complexes of (A) astilbin–Mpro, (B) engeletin–Mpro, and (C) myricitrin–Mpro, where, red and blue dots show the simulation’s illustration of protein conformational changes.

Figure 11

Graphical representation of Gibbs free energy landscape or the FEL of the (A) astilbin–Mpro, (B) engeletin–Mpro, and (C) myricitrin–Mpro complexes obtained from the dynamic simulation study.

Figure 12

The HOMO and LUMO molecular orbitals of the selected candidate drug molecules.