Rutin and flavone analogs as prospective SARS-CoV-2 main protease inhibitors: In silico drug discovery study

Coronavirus disease 2019 (COVID-19) is a new pandemic characterized by quick spreading and illness of the respiratory system. To date, there is no specific therapy for Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Flavonoids, especially rutin, have attracted considerable interest as a prospective SARS-CoV-2 main protease (M(pro)) inhibitor. In this study, a database containing 2017 flavone analogs was prepared and screened against SARS-CoV-2 M(pro) using the molecular docking technique. According to the results, 371 flavone analogs exhibited good potency towards M(pro) with docking scores less than −9.0 kcal/mol. Molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM/GBSA) binding energy calculations, were performed for the top potent analogs in complex with M(pro). Compared to rutin, PubChem-129-716-607 and PubChem-885-071-27 showed better binding affinities against SARS-CoV-2 M(pro) over 150 ns MD course with ΔG(binding) values of −69.0 and −68.1 kcal/mol, respectively. Structural and energetic analyses demonstrated high stability of the identified analogs inside the SARS-CoV-2 M(pro) active site over 150 ns MD simulations. The oral bioavailabilities of probable SARS-CoV-2 M(pro) inhibitors were underpinned using drug-likeness parameters. A comparison of the binding affinities demonstrated that the MM/GBSA binding energies of the identified flavone analogs were approximately three and two times less than those of lopinavir and baicalein, respectively. In conclusion, PubChem-129-716-607 and PubChem-885-071-27 are promising anti-COVID-19 drug candidates that warrant further clinical investigations.