Flavonoids as Potential Therapeutics Targeting JAK1 in Breast Cancer: A Comprehensive Computational Study

ABSTRACT Breast cancer remains a global health challenge due to high prevalence and therapeutic resistance, necessitating the discovery of novel targeted strategies. This study investigated flavonoids targeting the Janus kinase 1 (JAK1) protein within the JAK/STAT pathway, a key regulator of tumor progression. An initial library of 823 anticancer compounds was screened, from which 79 flavonoids were prioritized for computational analysis based on their therapeutic potential. High‐throughput docking using AutoDock Vina identified 49 candidates with strong binding affinities (≤ –8 kcal/mol). Following ADMET and drug‐likeness screening, icaritin, luteolin, and galangin were subjected to rigorous 500 ns molecular dynamics (MD) simulations using GROMACS, with tofacitinib serving as a clinical control. MD results definitively identified icaritin as the most potent inhibitor, with a binding free energy of –49.58 kcal/mol, significantly outperforming tofacitinib (–42.82 kcal/mol). Although luteolin exhibited a higher density of simultaneous hydrogen bonds analyzed via Visual Molecular Dynamics (VMD), icaritin maintained a more rigid and robust interaction profile, yielding superior thermodynamic stability. These findings establish icaritin as the primary lead compound for targeted JAK1 inhibition, with luteolin as a strong secondary candidate. This research provides a robust rationale for further validation to disrupt STAT activation and suppress breast cancer proliferation.