In silico evaluation of flavonoids as effective antiviral agents on the spike glycoprotein of SARS-CoV-2

Abstract

The novel coronavirus pandemic has spread over in 213 countries as of July 2020. Approximately 12 million people have been infected so far according to the reports from World Health Organization (WHO). Preventive measures are being taken globally to avoid the rapid spread of virus. In the current study, an in silico approach is carried out as a means of inhibiting the spike protein of the novel coronavirus by flavonoids from natural sources that possess both antiviral and anti-inflammatory properties. The methodology is focused on molecular docking of 10 flavonoid compounds that are docked with the spike protein of SARS-CoV-2, to determine the highest binding affinity at the binding site. Molecular dynamics simulation was carried out with the flavonoid-protein complex showing the highest binding affinity and highest interactions. The flavonoid naringin showed the least binding energy of -9.8 Kcal/mol with the spike protein which was compared with the standard drug, dexamethasone which is being repurposed to treat critically ill patients. MD simulation was carried out on naringin-spike protein complex for their conformational stability in the active site of the novel coronavirus spike protein. The RMSD of the complex appeared to be more stable when compared to that of the protein from 0.2 nm to 0.4 nm. With the aid of this in silico approach further in vitro studies can be carried out on these flavonoids against the novel coronavirus as a means of viral protein inhibitors.

Keywords: Antiviral; COVID-19, Coronavirus Disease 2019; CoVs, Coronaviruses; Covid-19; Docking; Flavonoids; MD simulations; PDB, Protein Data Bank; RMSD, Root Mean Square Deviation; RMSF, Root Mean Square Fluctuation; Rg, Radius of Gyration; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

Fig. 1

COVID-19 confirmed cases reported weekly by WHO region and worldwide deaths, 30 December 2019 through 04 October 2020.

Fig. 2

3-dimensional structures of Flavonoids and the structure of dexamethasone drug retrieved from PubChem.

Fig. 3

3-dimensional Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. PDB ID: 6m0j.

Fig. 4

Ramachandran plot of the spike protein showing 97.6% residues is favored region.

Fig. 5

Binding pocket (red color) obtained from CASTp tool along with the sequence which shows the highlighted residues forming the binding pocket.

Fig. 6

Column bar graph showing the negative binding energies (Kcal/mol) of each flavonoid with the spike protein active site.

Fig. 7

Two-dimensional representation of the best docking pose of naringin flavonoid with the binding amino acid residues of the spike protein of novel coronavirus.

Fig. 8

Pictorial 3D representaion of naringin flavonoid buried within the active pocket of the spike protein bound to the interacting binding residues.

Fig. 9

RMSD of 6m0j protein with bound ligand naringin in comparison with protein without any bound ligands.

Fig. 10

RMSF of the Cα atoms of (a) protein and (b) protein–ligand complex characterizes the atomic fluctuation during the 1 ns MD simulation.

Fig. 11

Radius of gyration (right) and Solvent accessible surface area (left) of protein–ligand complex during the 1000 ps time frame.

Fig. 12

Variation in hydrogen bond number with respect to simulation time.