一种使用α-碳酸酐酶寻找抗剂的计算方法。

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

作者信息

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

机构信息

Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, México.

Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88710, México.

出版信息

Med Chem. 2025;21(1):46-60. doi: 10.2174/0115734064310458240719071823.

DOI:10.2174/0115734064310458240719071823

PMID:39082172

Abstract

BACKGROUND

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

OBJECTIVE

The aim in this study was identify potential α-CA inhibitors with trypanocidal activity.

METHODS

A maximum common substructure (MCS) and molecular docking were used to carried out a ligand- and structure-based virtual screening of ZINC20 and MolPort databases. The compounds selected were evaluated in an model against the NINOA strain of , 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-CA and good biopharmaceutical and pharmacokinetic properties. C7, C9, and C21 had half-maximal inhibitory concentration (IC) values of 26, 61.6, and 49 μM, respectively, against NINOA strain epimastigotes of .

CONCLUSION

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

摘要

背景

尽管在过去四十年中做出了努力，但恰加斯病仍缺乏有效的药物治疗。由于碳酸酐酶（α-CA）在寄生虫生理过程中起着关键作用，它已成为设计新型抗寄生虫化合物的一个有吸引力的靶点。

目的

本研究的目的是鉴定具有杀锥虫活性的潜在α-CA抑制剂。

方法

使用最大公共子结构（MCS）和分子对接对ZINC20和MolPort数据库进行基于配体和结构的虚拟筛选。所选化合物在针对克氏锥虫NINOA菌株的模型中进行评估，并在小鼠巨噬细胞J774.2模型中测定细胞毒性。

结果

五种磺酰胺衍生物（C7、C9、C14、C19和C21）具有最高的对接分数（-6.94至-8.31 kcal/mol）。它们在α-CA的活性位点上显示出关键残基相互作用，并具有良好的生物药剂学和药代动力学性质。C7、C9和C21对克氏锥虫NINOA菌株前鞭毛体的半数抑制浓度（IC）值分别为26、61.6和49 μM。