Genistein as a Potential Breast Cancer Therapeutic: Computational Investigations Targeting EGFR and Oncogenic Pathways

ABSTRACT

Breast cancer (BC), a malignant disease responsible for high fatality worldwide, is characterized by EGFR overexpression or mutation, which contributes to tumor cell survival and progression. The present study explored the efficacy of Genistein in modulating EGFR using an integrated computational approach. Common targets of Genistein (SwissTargetPrediction) and BC (GeneCards) were identified, followed by PPI, GO, and KEGG enrichment analyses using STRING. The Genistein–targets–pathways network was constructed using Cytoscape 3.10.0. Docking, MM/GBSA binding free‐energy calculations, molecular dynamics (MD) simulations, and post‐MD analyses (PCA and FEL) were performed for Genistein and the reference inhibitor Afatinib against EGFR. Docking scores of Genistein (−8.96 kcal/mol) and Afatinib (−10.22 kcal/mol) demonstrated comparable binding within the EGFR ATP‐binding pocket, with Genistein retaining interactions with key catalytic residues. The MM/GBSA binding free‐energy of Genistein (−134.96 kcal/mol) and Afatinib (−137.92 kcal/mol) differed only marginally, indicating comparable binding stability within the EGFR domain. MD simulations, together with RMSD, RMSF, radius of gyration, SASA, PCA, and FEL analyses, confirmed the structural stability of the Genistein‐EGFR complex throughout the simulation. Collectively, these findings suggest that Genistein is a promising multitarget EGFR‐modulating compound that warrants further experimental validation through in vitro and in vivo studies.