Multi-Target Inhibition of Breast Cancer Receptors by Pomegranate Peel Phytochemicals: An Integrated Docking, MD Simulation, and DFT Study

Background

Breast cancer progression is governed by highly interconnected signaling networks involving receptor tyrosine kinases and hormone-responsive nuclear receptors, which collectively drive tumor heterogeneity, adaptive resistance, and therapeutic failure. Consequently, simultaneous modulation of multiple oncogenic pathways represents a rational strategy to improve treatment efficacy. In this study, a comprehensive in silico framework therapeutic failure was employed to investigate the multi-target inhibitory potential of selected pomegranate (Punica granatum) peel–derived phytochemicals against key breast cancer associated receptors.

Materials and Methods

Four bioactive compounds plantaginin, brevifolin, brevifolin carboxylic acid, and olivetolide were initially screened against Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor-2 (HER2), insulin-like growth factor-1 receptor (IGF-1R), progesterone receptor (PR), and Androgen Receptor (AR) using molecular docking. Based on binding affinity, interaction patterns, and receptor selectivity, plantaginin and brevifolin carboxylic acid emerged as the most promising candidates and were further subjected to molecular dynamics simulations to assess complex stability and conformational behavior under dynamic conditions. Principal component analysis was performed to evaluate ligand-induced collective motions, while density functional theory calculations were conducted to elucidate electronic properties and chemical reactivity. Pharmacokinetic feasibility and toxicological risk were assessed using in silico ADME and toxicity prediction platforms.

Results

Docking analyses demonstrated distinct receptor-selective polypharmacological behavior, wherein plantaginin exhibited preferential binding affinity and interaction stability toward EGFR, HER2, and AR, whereas brevifolin carboxylic acid showed comparatively stronger binding propensity toward IGF-1R and PR.

Conclusion

Collectively, these findings provide robust molecular-level evidence supporting the potential of pomegranate peel–derived phytochemicals as multi-target modulators of breast cancer–associated signaling pathways and establish a strong computational foundation for future experimental validation.