Taiyab Aaliya, Sulaimani Md Nayab, Rathi Aanchal, Khan Fazlurrahman, Hussain Afzal, Alajmi Mohamed F, Hassan Md Imtaiyaz
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
Department of Biotechnology, Faculty of Life Sciences, Jamia Millia Islamia, New Delhi, India.
J Mol Recognit. 2025 May;38(3):e70005. doi: 10.1002/jmr.70005.
Cancer cells exhibit elevated levels of reactive oxygen species, resulting in oxidative stress and DNA damage. To counteract this, many cancers upregulate the expression of MTH1 (MutT Homolog-1), a crucial enzyme that detoxifies oxidised nucleotide pools. Consequently, inhibiting MTH1 is a potential therapeutic strategy for managing DNA damage and cancer cell death. Here, we conducted a comprehensive computational screening of 3800 FDA-approved drugs to identify potential MTH1 inhibitors. Among these, Lumacaftor and Nilotinib were selected based on their strong binding affinity and pharmacokinetic profiles. Molecular dynamics simulations over 500 ns further validated the stable binding of these drugs to MTH1, suggesting their potential as effective inhibitors. Nilotinib, a well-known tyrosine kinase inhibitor (TKI), displayed strong binding affinity (Ka = 2.5 × 10) and potent MTH1 inhibitory activity (IC: 37.2 μM). Notably, this study is the first to establish the interaction between Nilotinib and MTH1, highlighting the dual potential of Nilotinib as an MTH1 inhibitor. The findings suggest that Nilotinib could be repurposed to enhance cancer therapy, particularly in combating drug resistance through the novel mechanism of MTH1 inhibition. This approach provides new avenues for tackling chemoresistance and improving therapeutic outcomes in cancer patients.
癌细胞表现出较高水平的活性氧，导致氧化应激和DNA损伤。为了应对这一情况，许多癌症上调了MTH1（MutT同源物-1）的表达，MTH1是一种关键酶，可对氧化的核苷酸池进行解毒。因此，抑制MTH1是管理DNA损伤和癌细胞死亡的一种潜在治疗策略。在此，我们对3800种FDA批准的药物进行了全面的计算筛选，以确定潜在的MTH1抑制剂。其中，鲁马卡托和尼洛替尼因其强大的结合亲和力和药代动力学特征而被选中。超过500纳秒的分子动力学模拟进一步验证了这些药物与MTH1的稳定结合，表明它们作为有效抑制剂的潜力。尼洛替尼是一种著名的酪氨酸激酶抑制剂（TKI），表现出强大的结合亲和力（Ka = 2.5×10）和强大的MTH1抑制活性（IC：37.2μM）。值得注意的是，本研究首次确立了尼洛替尼与MTH1之间的相互作用，突出了尼洛替尼作为MTH1抑制剂的双重潜力。研究结果表明，尼洛替尼可被重新用于增强癌症治疗，特别是通过抑制MTH1的新机制来对抗耐药性。这种方法为解决化疗耐药性和改善癌症患者的治疗效果提供了新途径。
