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: ۷O۹W) revealed several compounds exhibiting stronger binding affinities than the standard inhibitor verapamil (–۷.۸ kcal/mol). Among them, ۱۸β-glycyrrhetinic acid (–۹.۷ kcal/mol), glabridin (–۹.۳ kcal/mol), glabranin (–۹.۱ kcal/mol), and licoflavone A (–۸.۷ kcal/mol) showed the most stable interactions with key residues PHE۳۴۳, GLN۳۴۷, GLU۸۷۵, and TYR۳۱۰, 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.

کلیدواژه ها:

Glycyrrhiza glabra ، p-glycoprotein ، Multidrug Resistance ، Molecular docking ، ADMET analyses ، natural P-gp inhibitors