Khan Mohd Shahnawaz, Shamsi Anas, Zuberi Azna, Shahwan Moyad
Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.
Front Pharmacol. 2025 Aug 29;16:1619639. doi: 10.3389/fphar.2025.1619639. eCollection 2025.
The dual specificity mitogen-activated protein kinase kinase 1 (MEK1) is a critical node in the RAS-RAF-MEK-ERK signaling pathway, frequently dysregulated in cancers due to mutations in upstream regulators. Despite the development of MEK inhibitors, challenges such as on-target toxicities and drug resistance persist that emphasize the need for novel therapeutic strategies. Drug repurposing offers a fast and cost-effective alternative by leveraging existing FDA-approved compounds with established safety profiles. This study employed computational approaches to identify repurposed MEK1 inhibitors through structure-based virtual screening of 3,500 FDA-approved drugs. The MEK1 crystal structure was subjected to molecular docking using InstaDock, followed by biological activity prediction, interaction analysis, and 500-ns molecular dynamics (MD) simulations to assess stability. Radotinib and Alectinib exhibited superior docking scores (-10.5 and -10.2 kcal/mol), outperforming the reference MEK1 inhibitor Selumetinib (-7.2 kcal/mol). MD simulations revealed stable drug complexes, with lower root mean square deviation (RMSD) and fluctuations (RMSF) than Selumetinib. Principal component analysis and free energy landscapes corroborated their conformational stability, suggesting robust binding to MEK1's allosteric pocket. Radotinib interacted extensively with key residues, including Gly79 and Lys97 at the ATP-binding site, while Alectinib engaged critical residues such as Arg189 and His239. Their superior binding and conformational stability suggest the potential to overcome resistance and toxicity issues associated with existing MEK inhibitors. The structural and dynamic superiority of Radotinib and Alectinib over Selumetinib positions them as promising repurposed MEK1 inhibitors, potentially circumventing the clinical challenges of existing therapies. A limitation of this study is the absence of experimental validation, which will be addressed in future work. Experimental validation is essential to confirm their efficacy and safety in MEK1-linked malignancies.
双特异性丝裂原活化蛋白激酶激酶1（MEK1）是RAS-RAF-MEK-ERK信号通路中的关键节点，由于上游调节因子的突变，在癌症中经常发生失调。尽管开发了MEK抑制剂，但诸如靶向毒性和耐药性等挑战仍然存在，这突出了对新型治疗策略的需求。药物重新利用通过利用具有既定安全概况的现有FDA批准的化合物提供了一种快速且具有成本效益的替代方案。本研究采用计算方法，通过对3500种FDA批准的药物进行基于结构的虚拟筛选来识别重新利用的MEK1抑制剂。使用InstaDock对MEK1晶体结构进行分子对接，随后进行生物活性预测、相互作用分析和500纳秒的分子动力学（MD）模拟以评估稳定性。拉多替尼和阿来替尼表现出优异的对接分数（-10.5和-10.2千卡/摩尔），优于参考MEK1抑制剂司美替尼（-7.2千卡/摩尔）。MD模拟揭示了稳定的药物复合物，其均方根偏差（RMSD）和波动（RMSF）低于司美替尼。主成分分析和自由能景观证实了它们的构象稳定性，表明与MEK1的变构口袋有强大的结合。拉多替尼与关键残基广泛相互作用，包括ATP结合位点的Gly79和Lys97，而阿来替尼与Arg189和His239等关键残基相互作用。它们优越的结合和构象稳定性表明有可能克服与现有MEK抑制剂相关的耐药性和毒性问题。拉多替尼和阿来替尼相对于司美替尼的结构和动力学优势使其成为有前景的重新利用的MEK1抑制剂，有可能规避现有疗法的临床挑战。本研究的一个局限性是缺乏实验验证，这将在未来的工作中解决。实验验证对于确认它们在MEK1相关恶性肿瘤中的疗效和安全性至关重要。
