Evaluation of flavonoids as potential inhibitors of the SARS-CoV-2 main protease and spike RBD: Molecular docking, ADMET evaluation and molecular dynamics simulations

The 3CLpro main protease and the RDB spike (s) protein of SARS-CoV-2 are critical targets in the treatment of coronavirus 19 disease (COVID-19), as they are responsible for the COVID-19 replication and infection. With this in mind, Molecular docking of 26 natural compounds belonging to the flavonoid family with the 3CLpro and RBD sites of SARS-CoV-2 has been performed. The docking results revealed that the ligands Silibinin, Tomentin A, Tomentin B, 4'-O-methyldiplacone, Hesperidin Amentoflavone and Bilobetin act as a potential inhibitor of SARS-CoV-2 3CLpro, and that the ligands Herbacetin, Morin, Silibinin, Tomentin E, Amentoflavone, Bilobetin, Bai-calein and Quercetin can be potential inhibitors of SARS-CoV-2 RBD. It has been noticed that three ligands can inhibit both sites of SARS-CoV-2, indicating a great potential of these compounds to combat COVID-19. More-over, molecular docking has been validated by a new validation method based on visual inspiration. Evaluation of ADMET pharmacokinetic properties and the drug likeness in silico revealed that six compounds could be effective drugs against COVID-19. Finally, the docking results were verified by molecular dynamics simulations and MM-GBSA calculation to confirm the stability of hydrogen bonding interactions with crucial residues, which are essential to overcome SARS-CoV-2. These results could direct researchers toward plant-derived compounds that could be further investigated as therapeutic targets against COVID-19 replication and infection.