The Antiepileptic Drug Levetiracetam Inhibits Carbonic Anhydrase: In Vitro and In Silico Studies on Catalytically Active Human Isoforms.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-11-11 eCollection Date: 2024-12-12 DOI:10.1021/acsmedchemlett.4c00380

Luigi Cutarella, Mattia Mori, Claudiu T Supuran

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Abstract

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 in vitro and in silico. 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.

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抗癫痫药物左乙拉西坦抑制碳酸酐酶：催化活性人异构体的体外和计算机研究。

一些抗癫痫药物（aed）已被发现可以抑制人体碳酸酐酶（hCAs），为将aed用于治疗包括癌症在内的各种疾病铺平了道路。本文研究了左乙拉西坦的hCAs抑制作用，左乙拉西坦是一种高度处方的AED，不具有常见的锌结合基团。左乙莱西坦抑制所有测试的hCA，尽管与对照乙酰唑胺相比具有特定的特征，但对肿瘤相关的hCA IX和XII具有显着的疗效。分子对接和动力学（MD）模拟强调了与Zn（II）配位水的h键作为hCAs的主要锚点，以及与II相比，hCA同工型IX和XII的催化位点内的持续相互作用，这与实验数据相关。我们的研究结果可以解释为什么左乙拉西坦在临床上作为抗肿瘤药物对脑肿瘤引起的癫痫患者也有效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.