Rational design of flavonoid based potential inhibitors targeting SARS-CoV 3CL protease for the treatment of COVID-19

Abstract

The current outbreak of Coronavirus Disease 2019 (COVID-19) pandemic has reported thousands of deaths worldwide due to the rapid transmission rate and the lack of antiviral drugs and vaccinations. There is an urgent need to develop potential antiviral drug candidates for the prevention of COVID-19 infection. In the present study, a series of potential inhibitors targeting SARS-CoV 3CL protease were rationally designed by incorporating gamma lactam ring, and various fluoro substituted heterocyclic ring systems to the flavonoid scaffold. The prediction of drug-likeness, oral bioavailability, toxicity, synthetic accessibility, and ADMET properties was made by computational means. Quercetin was used as standard. The binding affinity of the ligands towards the 3CL protease target was examined using docking simulations. The designed ligands possess favourable pharmacokinetic and pharmacodynamic properties. Ligand L4, L8, and L14 appeared to be the lead compounds in the series and can be considered for further in-vivo and in-vitro validation.

Antiviral activity of chrysin and naringenin against porcine epidemic diarrhea virus infection

“…These two flavonoid compounds also might interfere with virus replication by inhibiting the activity of PLP2 protein, ultimately achieving an inhibitory effect on virus replication. Similar mechanism have also been confirmed in studies of other flavonoids’ effects on SARS-CoV and MERS-CoV ( 53 ).…”

“…These two flavonoid compounds also might interfere with virus replication by inhibiting the activity of PLP2 protein, ultimately achieving an inhibitory effect on virus replication. Similar mechanism have also been confirmed in studies of other flavonoids' effects on SARS-CoV and MERS-CoV (53). However, research on the effects of chrysin and naringenin on PEDV is still very limited, and there are few reported natural compounds with anti-PEDV activity.…”

Pharmacological Activities and Pharmacokinetics of Glycycoumarin

“…The 3C-like protease (3CLPro) is the main protease produced by the novel coronavirus (coronavirus disease 2019, COVID-19) (Bhati et al 2021 ), and inhibition of 3CLpro can effectively inhibit virus infection and replication. The predicted results of the latest study showed (Abdizadeh et al 2021 ) that 1 shows a better binding affinity to 3CLpro, with an optimal negative energy fraction, and interacts with one or two catalytic residues of 3CLpro (His41 and Cys145) through hydrophilic and hydrophobic bonds.…”

Potential inhibitory properties of structurally modified quercetin/isohamnetin glucosides against SARS-CoV-2 Mpro; molecular docking and dynamics simulation strategies

“…In a study conducted by Ref. [ 41 ]; quercetin when docked into the active site of the Mpro showed binding energy of −6.95 kcal/mol higher than the glucoside derivatives. Thus, the presence of the glucoside residue enhances the affinity of the ligand for the protein targets.…”