FLAVONOIDS AS POTENTIAL SARS-COV-2 Mpro INHIBITORS: AN IN- SILICO DOCKING AND ADME/T STUDY

Abstract

Background: The COVID-19 pandemic, caused by SARS-CoV-2, has created an urgent need for
effective antiviral therapeutics. The main protease (Mpro) of SARS-CoV-2 plays a critical role in viral
replication and is considered a promising target for drug development. Flavonoids, natural plant
compounds with proven antiviral properties, are explored here as potential inhibitors of SARS-CoV-2
Mpro.
Objective: To evaluate the binding affinity, drug-likeness, and ADMET profiles of selected flavonoids
and their derivatives against SARS-CoV-2 Mpro using in silico molecular docking and ADMET
analysis.
Methods: The crystal structure of SARS-CoV-2 Mpro (PDB ID: 6LU7) was retrieved from the Protein
Data Bank. Fifteen flavonoid compounds were screened for drug-likeness using Lipinski’s Rule of Five.
Active binding sites were identified using CASTp. Molecular docking was performed using AutoDock
4.2, and ADMET properties were predicted using admetSAR.
Results: Nine flavonoid compounds met Lipinski’s criteria and were subjected to docking studies.
Docking results showed that all screened flavonoids exhibited significant binding affinity with SARS-
CoV-2 Mpro, comparable to or better than the native ligand (PRD_002214). The compound 5,7-
dimethoxyflavanone-4′-O-β-D-glucopyranoside displayed the highest binding affinity (−8.68
kcal/mol) with an inhibition constant of 430.93 nM, indicating strong interaction with the active site
residues. ADMET analysis revealed favorable gastrointestinal absorption, blood-brain barrier
penetration, and non-carcinogenic profiles for most compounds.
Conclusion: The flavonoid compounds evaluated in this study demonstrate strong inhibitory potential
against SARS-CoV-2 Mpro and exhibit acceptable drug-like and ADMET properties. These natural
compounds could serve as promising lead molecules for further experimental validation and
development of antiviral drugs against COVID-19.