Arylcoumarin perturbs SARS-CoV-2 pathogenesis by targeting the S-protein/ACE2 interaction

Abstract

The vaccination drive against COVID-19 worldwide was quite successful. However, the second wave of infections was even more disastrous. There was a rapid increase in reinfections and human deaths due to the appearance of new SARS-CoV-2 variants. The viral genome mutations in the variants were acquired while passing through different human hosts that could escape antibodies in convalescent or vaccinated individuals. The treatment was based on oxygen supplements and supportive protocols due to the lack of a specific drug. In this study, we identified three lead inhibitors of arylated coumarin derivatives 4,6,8-tri(naphthalen-2-yl)-2H-chromen-2-one (NF1), 8-(4-hydroxyphenyl)-4,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF12) and 8-(4-hydroxyphenyl)-3,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF-13) that showed higher binding affinity towards the junction of SARS-CoV-2 spike glycoprotein (S-protein) and human angiotensin-converting enzyme 2 (ACE2) receptor. Using molecular docking analysis, we identified the putative binding sites of these potent inhibitors. Notably, molecular dynamics (MD) simulation and MM-PBSA studies confirmed that these inhibitors have the potential ability to bind Spike-protein/ACE2 protein complex with minimal energy. Further, the two major concerns are an adaptive mutation of spike proteins- N501Y and D614G which displayed strong affinity towards NF-13 in docking analysis. Additionally, in vitro and in vivo studies are required to confirm the above findings and develop the inhibitors as potential drugs against SARS-CoV-2.

Figure 1

Binding site of NF-1, NF-12, and NF-13 on S-protein-ACE2 complex. (A) The binding site of NF-1, NF-12, and NF-13 on the S-protein-ACE2 receptor complex. (B) The putative binding site of NF-1, NF-12, and NF-13 on the S-protein-ACE2 receptor complex. (C) The zoomed view of the binding site of NF-1 on the S-protein-ACE2 receptor complex. (D) The interacting amino acid residues of ACE2 with NF-1. (E) The zoomed view of the binding site of NF-12 on the S-protein-ACE2 receptor complex. (F) The interacting amino acid residues of ACE2 with NF-12. (G) The zoomed view of the binding site of NF-13 on the S-protein-ACE2receptor complex. (H) The interacting amino acid residues of ACE2 with NF-13.

Figure 2

The backbone C^α-RMSD plots reflecting the conformational stabilities of ACE2 (black) and docked complexes with ligands, NF1 (blue), NF12 (red), and NF13 (green). A similar color scheme is used to represent the plots for protein and protein–ligand complexes from Figs. 2, 3, 4, 5, 6 and 7.

Figure 3

Time evolution plots of the radius of gyration (Rg) ofACE2 and protein–ligand complexes, ACE2-NF1, ACE2-NF12, and ACE2-NF13.

Figure 4

RMSF plots of ACE2 and docked complexes, ACE2-NF1, ACE2-NF12, and ACE2-NF13.

Figure 5

The time evolution plots of H-bond interactions between ACE2 with ligands NF1 (blue), NF12 (red), and NF13 (green).

Figure 6

Binding free energy (ΔG_bind) estimation of ligands, NF1, NF12, and NF13 with ACE2, using MM-PBSA.

Figure 7

Binding free energy (ΔG_bind) estimation of ligands, NF1, NF12, and NF13 with ACE2, using MM-GBSA.

Figure 8

Binding energy contribution of the active site amino acids of ACE2 involve in interaction with the ligands (A) NF1 (B) NF12 and (C) NF13.