Synthetic flavonoids as potential antiviral agents against SARS-CoV-2 main protease

Abstract

The COVID-19 pandemic has claimed more than a million lives worldwide within a short time span. Due to the unavailability of specific antiviral drugs or vaccine, the infections are causing panic both in general public and among healthcare providers. Therefore, an urgent discovery and development of effective antiviral drug for the treatment of COVID-19 is highly desired. Targeting the main protease (M pro) of the causative agent, SARS-CoV-2 has great potential for drug discovery and drug repurposing efforts. Published crystal structures of SARS-CoV-2 M pro further facilitated in silico investigations for discovering new inhibitors against M pro. The present study aimed to screen several libraries of synthetic flavonoids and benzisothiazolinones as potential SARS-CoV-2 M pro inhibitors using in silico methods. The short-listed compounds after virtual screening were filtered through SwissADME modeling tool to remove molecules with unfavorable pharmacokinetics and medicinal properties. The drug-like molecules were further subjected to iterative docking for the identification of top binders of SARS-CoV-2 M pro. Finally, molecular dynamic (MD) simulations and binding free energy calculations were performed for the evaluation of the dynamic behavior, stability of protein-ligand complex, and binding affinity, resulting in the identification of thioflavonol, TF-9 as a potential inhibitor of M pro. The computational studies further revealed the binding of TF-9 close to catalytic dyad and interactions with conserved residues in the S1 subsite of the substrate binding site. Our in-silico study demonstrated that synthetic analogs of flavonoids, particularly thioflavonols, have a strong tendency to inhibit the main protease M pro , and thereby inhibit the reproduction of SARS-CoV-2.

Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis

“…Several studies have reported that rutin, a flavonol glycoside, has high efficacy as a potent inhibitor to treat COVID-19 infection and noncovalent interact with the heteroatoms of amino acids of the M pro ’s active sit ( Ibrahim et al, 2021 ). Batool et a l identified TF-9, a thioflavonol, as a highly promising inhibitor of SARS-CoV-2 M pro with predicted binding energy of -8.7 kcal/mol from 101 synthetic flavonols ( Batool et al, 2020 ). Quercetin was identified as reasonably potent inhibitor of SARS-CoV-2 3CLpro with Ki∼7 μM from a small chemical library ( Abian et al, 2020 ).…”

Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

“…Arbutin, terbutaline, barnidipine, tipiracil, and aprepitant were identified as potential hits forming different hydrophilic, hydrophobic, and electrostatic interactions with M pro ( Baby et al, 2020 ). Thioflavonol is a synthetic flavonoid analog that showed a strong binding with the conserved residues in the S1 subsite ( Batool et al, 2020 ).…”

Promising Antiviral Activities of Natural Flavonoids against SARS-CoV-2 Targets: Systematic Review

“…Fayyaz et al screened several flavonoids and identified three potentially active flavonoids, whose activities against SARS-CoV-2 M pro were in the order of rhodiolin > baicalin > silymarin based on their binding energy (−9.05, −8.85, −8.71 kcal/mol respectively) and dissociation constant (0.23, 0.33, 0.41 µm, respectively) using molecular docking and simulation studies [147]. Thioflavonol also inhibits Mpro [148] along with other flavonoids such as apigenin, daidzein, quercetin, kaempferol, luteolin, epigallocatechin, and kaempferol using molecular docking and simulation analysis [104].…”