In Silico Screening and Validation of Natural Components as Novel P-glycoprotein Inhibitors to Enhance the Bioavailability of Cancer Drugs

Abstract

Background: Multidrug resistance in cancer arises when p-glycoprotein is overexpressed, actively expelling chemotherapeutic agents from cancer cells, thereby lowering their intracellular concentrations and diminishing the effectiveness of conventional therapies. However, in silico and docking-based screening of natural compounds offers a promising approach to identify selective, low-toxicity p-glycoprotein inhibitors that could help restore the efficacy of these drugs. Aim: The objective of this study was to use an in silico approach to study the potential of spice constituents as p-glycoprotein inhibitors, with the possibility that they may increase the bioavailability of co-administered cancer medications by decreasing their efflux from cancer cells. Methods: Virtual screening was employed to screen 16 bioactive components from 9 spices for their potential to interact with p-glycoprotein. The binding affinity and binding stability of these interactions were predicted using molecular docking and molecular dynamics simulations in the Biovia Discovery Studio software. Results: 7 components were identified with high binding affinities for p-glycoprotein, suggesting their potential as inhibitors. The compounds with the highest binding affinities for p-glycoprotein were hydroxymatairesinol, gingerenone-A, curcumin, and pinoresinol. Conclusion: The results of this study have proposed that hydroxymatairesinol from Sesamum indicum and gingerenone-A from Zingiber officinale, may be considered potential inhibitors of p-glycoprotein. Major Findings: The in silico analysis identified seven spice-derived compounds with strong predicted binding affinities toward p-glycoprotein, with Hydroxymatairesinol (from sesame) and GingerenoneA (from ginger) among the top binders, suggesting they may serve as promising, low-toxicity p-glycoprotein inhibitors to enhance chemotherapeutic drug retention in cancer cells.