A Computational Approach to Elucidate the Interactions of Chemicals From Artemisia annua Targeted Toward SARS-CoV-2 Main Protease Inhibition for COVID-19 Treatment

Abstract

The inhibitory potential of Artemisia annua, a well-known antimalarial herb, against several viruses, including the coronavirus, is increasingly gaining recognition. The plant extract has shown significant activity against both the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the novel SARS-CoV-2 that is currently ravaging the world. It is therefore necessary to evaluate individual chemicals of the plant for inhibitory potential against SARS-CoV-2 for the purpose of designing drugs for the treatment of COVID-19. In this study, we employed computational techniques comprising molecular docking, binding free energy calculations, pharmacophore modeling, induced-fit docking, molecular dynamics simulation, and ADMET predictions to identify potential inhibitors of the SARS-CoV-2 main protease (M^pro) from 168 bioactive compounds of Artemisia annua. Rhamnocitrin, isokaempferide, kaempferol, quercimeritrin, apigenin, penduletin, isoquercitrin, astragalin, luteolin-7-glucoside, and isorhamnetin were ranked the highest, with docking scores ranging from -7.84 to -7.15 kcal/mol compared with the -6.59 kcal/mol demonstrated by the standard ligand. Rhamnocitrin, Isokaempferide, and kaempferol, like the standard ligand, interacted with important active site amino acid residues like HIS 41, CYS 145, ASN 142, and GLU 166, among others. Rhamnocitrin demonstrated good stability in the active site of the protein as there were no significant conformational changes during the simulation process. These compounds also possess acceptable druglike properties and a good safety profile. Hence, they could be considered for experimental studies and further development of drugs against COVID-19.

Keywords: Artemisia annua; SARS-CoV-2; coronavirus; isokaempferide; kaempferol; main protease (Mpro); rhamnocitrin.

Figure 1

The 10 top-scoring compounds of Artemisia annua against SARS-CoV-2 main protease.

Figure 2

The 3D view of the molecular interaction of (A) K36, (B) Rhamnocitrin, (C) Isokaempferide, and (D) Kaempferol with SARS-CoV-2 main protease.

Figure 3

The 2D view of the molecular interaction of (A) K36, (B) Rhamnocitrin, (C) Isokaempferide, and (D) Kaempferol with SARS-CoV-2 main protease.

Figure 4

The binding free energy MM-GBSA (ΔG_bind) vs. the docking score (kcal/mol) of 168 compounds of Artemisia annua against SARS-CoV-2 main protease.

Figure 5

The receptor-ligand complex pharmacophore models of (A) K36, (B) 7-Methylkaempferol, (C) 3-Methylkaempferol, and (D) Kaempferol on SARS-CoV-2 main protease.

Figure 6

Molecular interactions of Rhamnocitrin with SARS-CoV-2 main protease from the induced fit docking.

Figure 7

(A) RMSD time series and histogram for Rhamnocitrin in the active site of SARS-CoV-2 main protease. (B) SARS-CoV-2 main protease RMSF(Å) vs. the residue position.

Figure 8

PCA results, comprising graphs of PC2 vs. PC1, PC2 vs. PC3, PC3 vs. PC1, and an eigenvalue rank plot with the cumulative variance annotated for each data point. (A) PCA plots colored from blue to red in order of time; (B) PCA Plots showing two different clusters colored black and red. (C) Residue-wise loadings for PC1 (black) and PC2 (blue).