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In Silico-Guided Identification of New Potent Inhibitors of Carbonic Anhydrases Expressed in Vibrio cholerae
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-09-01 , DOI: 10.1021/acsmedchemlett.0c00417
Francesca Mancuso 1 , Laura De Luca 1 , Andrea Angeli 2 , Emanuela Berrino 2 , Sonia Del Prete 3 , Clemente Capasso 3 , Claudiu T Supuran 2 , Rosaria Gitto 1
Affiliation  

Carbonic anhydrases from Vibrio cholerae (VchCAs) play a significant role in bacterial pathophysiological processes. Therefore, their inhibition leads to a reduction of gene expression virulence and bacterial growth impairment. Herein, we report the first ligand-based pharmacophore model as a computational tool to study selective inhibitors of the β-class of VchCA. By a virtual screening on a collection of sulfonamides, we retrieved 9 compounds that were synthesized and evaluated for their inhibitory effects against VchCAβ as well as α- and γ-classes of VchCAs and selectivity over human ubiquitous isoforms hCA I and II. Notably, all tested compounds were active inhibitors of VchCAs. The N-(4-sulfamoylbenzyl)-[1,1′-biphenyl]-4-carboxamide (20e) stood out as the most exciting inhibitor toward the β-class (Ki = 95.6 nM), also showing a low affinity against the tested human isoforms. By applying docking procedures, we described the binding mode of the inhibitor 20e within the catalytic cavity of the modeled open conformation of VchCAβ.

中文翻译:

在硅胶引导下鉴定霍乱弧菌中表达的碳酸酐酶的新型强效抑制剂

来自霍乱弧菌(VchCA) 的碳酸酐酶在细菌病理生理过程中起重要作用。因此,它们的抑制导致基因表达毒力的降低和细菌生长障碍。在此,我们报告了第一个基于配体的药效团模型作为研究 VchCA β 类选择性抑制剂的计算工具。通过对一系列磺胺类药物的虚拟筛选,我们检索了 9 种化合物,这些化合物已合成并评估了它们对 VchCAβ 以及 α 和 γ 类 VchCA 的抑制作用以及对人类普遍存在的同种型 hCA I 和 II 的选择性。值得注意的是,所有测试的化合物都是 VchCA 的活性抑制剂。所述ñ - (4- sulfamoylbenzyl) - [1,1'-联苯] -4-甲酰胺(20E) 作为最令人兴奋的 β 类抑制剂 ( K i = 95.6 nM) 脱颖而出,对测试的人类亚型也显示出低亲和力。通过应用对接程序,我们描述了抑制剂20e在建模的 VchCAβ 开放构象的催化腔内的结合模式。
更新日期:2020-09-01
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