Yalaza Cem, Antmen Serife Efsun, Acuner Saliha Ece, Oz Hasan, Bulut Ecem, Canacankatan Necmiye
Department of Biochemistry, Faculty of Pharmacy, Başkent University, Ankara, Turkey.
Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
Discov Oncol. 2025 Jun 16;16(1):1122. doi: 10.1007/s12672-025-02792-w.
Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase receptor involved in cell growth and differentiation. Targeting HER2 is a critical strategy in HER2-positive breast cancer treatment. Despite advancements in HER2-targeted therapies, drug resistance and side effects remain significant challenges. Therefore, identifying novel HER2 inhibitors with the potential to overcome resistance mechanisms while maintaining favorable drug-like properties is essential. Identifying novel HER2 inhibitors with high binding affinity and favorable drug-like properties is essential for overcoming these limitations. This study employed molecular docking and molecular dynamics simulations to evaluate the binding potential of plant-derived and synthetic compounds against HER2. The most promising candidates were further analyzed using ADMET profiling and binding free energy calculations to assess their drug-likeness and binding free energy. Among the tested compounds, axitinib, prunetin, and silymarin demonstrated strong HER2-binding affinities comparable to established inhibitors such as TAK-285 and lapatinib. Molecular dynamics simulations revealed that prunetin formed the most stable HER2-ligand complex, while axitinib exhibited the lowest binding free energy, indicating a strong interaction potential. ADMET analysis confirmed axitinib and prunetin as favorable drug candidates, whereas silymarin exhibited lower intestinal absorption. In conclusion, axitinib and prunetin emerged as promising HER2 inhibitors that may offer therapeutic advantages by addressing both drug resistance and toxicity concerns in HER2-positive breast cancer treatment. Prunetin, with its lower toxicity and higher stability, presents a safer therapeutic option, whereas axitinib offers high binding affinity. These findings suggest that these compounds could help overcome resistance and side effects associated with current HER2-targeted therapies.
人表皮生长因子受体2（HER2）是一种参与细胞生长和分化的酪氨酸激酶受体。靶向HER2是HER2阳性乳腺癌治疗的关键策略。尽管HER2靶向治疗取得了进展，但耐药性和副作用仍然是重大挑战。因此，识别具有克服耐药机制潜力且保持良好类药性质的新型HER2抑制剂至关重要。识别具有高结合亲和力和良好类药性质的新型HER2抑制剂对于克服这些局限性至关重要。本研究采用分子对接和分子动力学模拟来评估植物源和合成化合物与HER2的结合潜力。使用ADMET分析和结合自由能计算对最有前景的候选物进行进一步分析，以评估它们的类药性质和结合自由能。在测试的化合物中，阿西替尼、柚皮素和水飞蓟宾表现出与已确立的抑制剂如TAK-285和拉帕替尼相当的强HER2结合亲和力。分子动力学模拟表明，柚皮素形成了最稳定的HER2-配体复合物，而阿西替尼表现出最低的结合自由能，表明其具有很强的相互作用潜力。ADMET分析证实阿西替尼和柚皮素是良好的候选药物，而水飞蓟宾的肠道吸收较低。总之，阿西替尼和柚皮素成为有前景的HER2抑制剂，它们可能通过解决HER2阳性乳腺癌治疗中的耐药性和毒性问题而提供治疗优势。柚皮素毒性较低且稳定性较高，是一种更安全的治疗选择，而阿西替尼具有高结合亲和力。这些发现表明，这些化合物有助于克服与当前HER2靶向治疗相关的耐药性和副作用。
