Pantnagar Journal of Research

Abstract

Breast cancer remains the most prevalent malignancy among women and a major contributor to global cancer mortality. The survival of breast cancer stem cells (BCSCs), regulated largely by the canonical Wnt/β-catenin signaling pathway, drives therapeutic resistance, metastasis, and tumor relapse. Contemporary chemotherapeutic strategies intended to target the transformed cells have not been proven to be effective due to recurrence, drug resistance, and poor prognosis, besides substantial toxicity to normal tissue too. Natural products including curcumin, a polyphenolic compound derived from Curcuma longa have been shown to possess pleiotropic therapeutic and chemopreventive properties along with their potential to inhibit Wnt-mediated stemness by suppressing the β-catenin, a key effector of the Wnt signaling pathway. The poor bioavailability and rapid metabolic degradation of curcumin have restricted its therapeutic use, thereby prompting the synthesis of curcumin-natural product conjugates. The present study employed an in-silico approach to analyse curcumin conjugates targeting β-catenin. A panel of ligand molecules, including curcumin, p-coumaric acid, its conjugate, and a reference β-catenin inhibitor (R9Q) were selected for the molecular docking process against the target protein, β-catenin. Molecular docking and interaction analysis revealed that the designed conjugates displayed improved binding affinity, and stability compared to native curcumin. These findings support the rational design of natural product-based conjugates as potential therapeutic leads targeting Wnt/β-catenin signaling in breast cancer stem cells.