Flavonoids as Potential Therapeutics Targeting JAK1 in Breast Cancer: A Comprehensive Computational Study
ChemistrySelect, cilt.11, sa.17, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 11 Sayı: 17
- Basım Tarihi: 2026
- Doi Numarası: 10.1002/slct.202506326
- Dergi Adı: ChemistrySelect
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Academic Search Ultimate (EBSCO)
- Anahtar Kelimeler: breast cancer, computational drug design, flavonoids, JAK/STAT pathway, JAK1 protein
- Sağlık Bilimleri Üniversitesi Adresli: Evet
Özet
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.