Molecular Docking and ADMET-Based Discovery of Glycyrrhiza glabra Bioactives as P-Glycoprotein Inhibitors for Combating Multidrug Resistance

This study employed an extensive computational approach to identify
bioactive compounds from Glycyrrhiza glabra (licorice) with potential
inhibitory activity against P-glycoprotein (P-gp), a key efflux transporter
associated with multidrug resistance (MDR) in cancer. Twenty
phytochemicals, including triterpenoid saponins, flavonoids, and chalcones,
were evaluated using molecular docking and in silico ADMET analyses.
Docking studies using AutoDock Vina against the human P-gp structure (PDB
ID: 7O9W) revealed several compounds exhibiting stronger binding affinities
than the standard inhibitor verapamil (–7.8 kcal/mol). Among them, 18β
glycyrrhetinic acid (–9.7 kcal/mol), glabridin (–9.3 kcal/mol), glabranin (–9.1
kcal/mol), and licoflavone A (–8.7 kcal/mol) showed the most stable
interactions with key residues PHE343, GLN347, GLU875, and TYR310,
crucial for substrate recognition and transport inhibition. ADMET analyses
indicated that glabridin, glabranin, and licoflavone A possess high
gastrointestinal absorption, non-hepatotoxicity, and favorable oral
bioavailability, satisfying Lipinski and Veber’s drug-likeness criteria.
Conversely, glycosylated saponins displayed lower permeability, but minimal
toxicity, suggesting potential combinatorial benefits. Overall, glabridin,
glabranin, and licoflavone A have emerged as promising natural P-gp
inhibitors capable of reversing MDR in cancer, meriting further in vitro and in
vivo validation.