Molecular docking, molecular dynamic and drug-likeness studies of natural flavonoids as inhibitors for SARS-CoV-2 main protease (Mpro)

The emergence of the global pandemic COVID-19 lead to a huge demand for the therapeutic agent to
combat the disease. Since the FDA approval of some of HIV-1 main protease inhibitors such as ritonavir lopinavir to
treat COVID-19, the investigation of anti-HIV inhibitor to inhibit SARS-CoV-2 main protease (Mpro) is getting
considerably much attention. This study evaluates the potency of sixteen selected natural flavonoids which were
previously reported active to block HIV-1 protease as potential inhibitors of SARS-CoV-2 Mpro. The molecular docking
and dynamic study were completed to know the binding affinity and stability of the protein-ligand complex via docking
study along with molecular dynamic simulations. Moreover, drug-likeness was also evaluated through via ADMET
evaluation. This study revealed robinin (6), a flavonol molecule with linked to galactose-rhamnose at C3 and rhamnose
molecule at C7, exhibited the highest binding affinity (-9 kcal/mol) among others. The amino acids that interacted with
robinin were Asn142; Gly143; Arg188; Thr190. The binding affinity of robinin surpassed the binding affinity of ritonavir
(-7.7 kcal/mol) and lopinavir (-8.2 kcal/mol). The replacement of the hydroxyl group from the flavonoid skeleton at C7, C-4’ was proposed to affect the binding affinity. The free hydroxyl group particularly in A ring and the position of
the hydroxyl group were important to improve the binding affinity. The molecular dynamic simulation showed the
stability of Mpro-robinin during the simulation period. The ADME evaluation referring to Lipinski`s rule of 5 revealed
that the flavonoids (2,5,6,9,10,13,14,15) show low oral bioavailability and absorption. Robinin exhibited a good druglikeness score (value:1) with an unconcerned level of acute toxicity. From this study, it was concluded that robinin
showed the most potent natural flavonoids studied to inhibit SASR-CoV-2 Mpro by both docking study and ADME/tox
properties evaluation