Cutarella Luigi, Mori Mattia, Supuran Claudiu T
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Sesto Fiorentino, 50019 Florence Italy.
ACS Med Chem Lett. 2024 Nov 11;15(12):2133-2139. doi: 10.1021/acsmedchemlett.4c00380. eCollection 2024 Dec 12.
Several antiepileptic drugs (AEDs) have been found to inhibit human carbonic anhydrases (hCAs), paving the way for repurposing AEDs for the treatment of various diseases, including cancer. Here, the hCAs inhibitory effects of levetiracetam, a highly prescribed AED that does not bear a common zinc-binding group, were investigated and . Levetiracetam inhibited all tested hCAs, although with a specific profile compared to the reference acetazolamide, with remarkable efficacy against tumor-associated hCA IX and XII. Molecular docking and dynamics (MD) simulations emphasized H-bonding to the Zn(II)-coordinated water as a major anchor point for hCAs, as well as a persistent interaction within the catalytic site of hCA isoforms IX and XII compared to II, which correlates with experimental data. Our results may explain why levetiracetam is also clinically effective as an antitumor agent in patients developing epilepsy as a consequence of brain tumors.
已发现几种抗癫痫药物（AEDs）可抑制人碳酸酐酶（hCAs），为将AEDs重新用于治疗包括癌症在内的各种疾病铺平了道路。在此，对左乙拉西坦（一种未带有常见锌结合基团的高处方量AED）的hCAs抑制作用进行了研究。左乙拉西坦抑制了所有测试的hCAs，尽管与参考药物乙酰唑胺相比具有特定的作用模式，对肿瘤相关的hCA IX和XII具有显著疗效。分子对接和动力学（MD）模拟强调与Zn（II）配位水形成氢键是hCAs的主要锚定点，以及与hCA同工酶II相比，hCA同工酶IX和XII催化位点内的持续相互作用，这与实验数据相关。我们的结果可能解释了为什么左乙拉西坦在因脑肿瘤而患癫痫的患者中作为抗肿瘤药物在临床上也有效。
