A Computational Approach Using α-Carbonic Anhydrase to Find Anti-Trypanosoma cruzi Agents.

IF 1.9 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Pub Date : 2024-07-30 DOI:10.2174/0115734064310458240719071823

Eyra Ortiz-Pérez, Domingo Mendez-Alvarez, Alfredo Juarez-Saldivar, Adriana Rodriguez-Moreno, Mariana De Alba-Alvarado, Alonzo Gonzalez-Gonzalez, Karina Vazquez, Ana Veronica Martinez-Vazquez, Benjamin Nogueda-Torres, Edgar E Lara-Ramírez, Alma D Paz-Gonzalez, Gildardo Rivera

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引用次数: 0

Abstract

Background: Chagas disease has an ineffective drug treatment despite efforts made over the last four decades. The carbonic anhydrase of Trypanosoma cruzi (α-TcCA) has emerged as an interesting target for the design of new antiparasitic compounds due to its crucial role in parasite processes.

Objective: The aim of this study was to identify potential α-TcCA inhibitors with trypanocide activity.

Method: A maximum common substructure (MCS) and molecular docking were used to carry out a ligand- and structure-based virtual screening of ZINC20 and MolPort databases. The compounds selected were evaluated in an in vitro model against the NINOA strain of Trypanosoma cruzi, and cytotoxicity was determined in a murine model of macrophage cells J774.2.

Results: Five sulfonamide derivatives (C7, C9, C14, C19, and C21) had the highest docking scores (-6.94 to -8.31 kcal/mol). They showed key residue interactions on the active site of the α-TcCA and good biopharmaceutical and pharmacokinetic properties. C7, C9, and C21 had half-maximal inhibitory concentration (IC50) values of 26, 61.6, and 49 μM, respectively, against NINOA strain epimastigotes of Trypanosoma cruzi.

Conclusion: Compounds C7, C9, and C21 showed trypanocide activity; therefore, these results encourage the development of new trypanocidal agents based on their scaffold.

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利用α-碳酸酐酶寻找抗克鲁斯锥虫药物的计算方法

背景：尽管过去四十年来人们一直在努力治疗南美锥虫病，但药物治疗效果不佳。由于克氏锥虫的碳酸酐酶（α-TcCA）在寄生虫过程中起着至关重要的作用，因此它已成为设计新型抗寄生虫化合物的一个有趣靶点：本研究旨在鉴定具有杀锥虫活性的潜在 α-TcCA 抑制剂：方法：在 ZINC20 和 MolPort 数据库中，使用最大通用亚结构（MCS）和分子对接技术进行配体和结构虚拟筛选。筛选出的化合物在体外模型中针对克氏锥虫 NINOA 菌株进行了评估，并在小鼠巨噬细胞模型 J774.2 中测定了细胞毒性：五个磺酰胺衍生物（C7、C9、C14、C19 和 C21）的对接得分最高（-6.94 至 -8.31 kcal/mol）。它们在 α-TcCA 的活性位点上显示出关键残基的相互作用，并具有良好的生物制药和药代动力学特性。C7、C9和C21对克氏锥虫NINOA菌株表皮原虫的半数最大抑制浓度（IC50）分别为26、61.6和49 μM：结论：化合物 C7、C9 和 C21 具有杀锥虫活性；因此，这些结果鼓励人们以它们的支架为基础开发新的杀锥虫药物。

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

Medicinal Chemistry 医学-医药化学

CiteScore

4.30

自引率

4.30%

发文量

109

审稿时长

12 months

期刊介绍： Aims & Scope Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.