Computational Exploration of Naturally Occurring Flavonoids as TGF‐β Inhibitors in Breast Cancer: Insights from Docking and Molecular Dynamics Simulations and In‐vitro Cytotoxicity Study

Abstract Breast cancer is a global health concern, demanding innovative treatments. Targeting the Transforming Growth Factor‐beta (TGF‐β) signaling pathway, pivotal in breast cancer, is a promising approach. TGF‐β inhibits proliferation via G1 phase cell cycle arrest, acting as a suppressor initially, but in later stages, it promotes progression by enhancing motility, invasiveness, and metastasis formation. This study explores naturally occurring flavonoids′ interactions with TGF‐β. Using molecular docking against the protein‘s crystal structure (PDB Id: 1PY5), Gossypin showed the highest docking score and underwent molecular dynamics simulation, revealing complex flexibility and explaining how flavonoids impede TGF‐β signaling in breast cancer. ADMET predictions adhered to Lipinski's rule of Five. Insights into flavonoid‐TGF‐β binding offer a novel angle for breast cancer treatment. Flavonoids having a good docking score like gossypin, morin, luteolin and taxifolin shown potent cytotoxic effect on breast cancer cell line, MCF‐7. Understanding these interactions could inspire flavonoid‐based therapies targeting TGF‐β to halt breast cancer growth. These findings pave the way for personalized, targeted breast cancer therapies, offering hope against this formidable disease.