Dietary polyphenols mitigate SARS-CoV-2 main protease (Mpro)-Molecular dynamics, molecular mechanics, and density functional theory investigations

Abstract

The recent evolution of the SARS-like Coronavirus has ravaged the world. The deadly virus has claimed over millions of lives across the world and hence highlights the need to develop effective therapeutic drugs to contain the disease posed by this parasite. In this study, the inhibitory potential of fifty (50) dietary polyphenols against Coronavirus (SARS-CoV-2) main protease (Mpro) was conducted using the Autodock Vina Molecular docking tool. In the virtual screening process, the binding affinity of Remdesivir (-7.7 kcal/mol) currently used to treat COVID-19 patients was set as the cut-off value to screen out less probable inhibitors. Ellagic acid, Kievitone, and Punicalin were the only promising ligands with binding affinities (-8.9 kcal/mol, -8.0 kcal/mol and -7.9 kcal/mol respectively) lower than the set cut-off value. Furthermore, we validated Ellagic acid and Kievitone efficacy by subjecting them to molecular dynamics simulation and further stability was assessed at the molecular mechanics and quantum levels. The overall analysis indicates both compounds demonstrate higher stability and inhibitory potential to bind to the crucial His41 and Cys145 catalytic dyad of Mpro than the standard drug. However, further analysis of punicalin after evaluating its docking score was not conducted as the ligand pharmacokinetics properties suggests it could pose serious adverse effect to the health of participants in clinical trials. Hence, we employed a more safe approach by filtering out the compound during this study. Conclusively, while Ellagic acid and kievitone polyphenolic compounds have been demonstrated to be promising under this in silico research, further studies are needed to substantiate their clinical relevance.

Keywords: ADMET, absorption, distribution, metabolism, excretion, and toxicity; GROMACS, GROningen MAchine for chemical simulations; HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital; MM-PBSA, molecular mechanics Poisson–Boltzmann Surface Area; Molecular docking; Molecular dynamics; Molecular mechanics; Mpro, main protease; ORF, open reading frame; Quantum mechanics; SARS-COV2 Mpro inhibitors.

Graphical abstract

Fig. 1

3D structure of SARS-COV2 Mpro and A. Ellagic acid B. Kievitone C. Punicalin D. Remdesivir conventional hydrogen bonds (Green), carbon hydrogen bonds (cyan) and hydrophobic (pink) 2D interactions with SARS-COV-2 Main protease residues.

Fig. 2

Superimposed RMSD spectrum of 6LU7 (Apoprotein), 6LU7-Ela, 6LU7-Kie and 6LU7-Rem.

Fig. 3

Superimposed RMSF spectrum of 6LU7 (Apoprotein), 6LU7-Ela, 6LU7-Kie and 6LU7-Rem.

Fig. 4

Represents the intermolecular H-bond spectrum of 6LU7-Ela, 6LU7-Kie and 6LU7-Rem.

Fig. 5

ROG Spectrum of 6LU7, 6LU7-Ela, 6LU7-Kie and 6LU7-Rem.

Fig. 6

MM-PBSA Binding free energy contribution of individual residue of 6LU7 in complex with A.Ela B.Kie C.Rem.

Fig. 7

The Highest occupied molecular orbital (HOMO) energy, Lowest occupied molecular orbital (LUMO) energy, and the molecular electrostatic potential (MEP).