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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. Communicated by Ramaswamy H. Sarma

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