Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action.,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-10 , DOI: 10.1021/acs.jmedchem.0c00733
Alessandro Bonardi _{1,

2} , Alessio Nocentini _{1,

2} , Silvia Bua ₁ , Jacob Combs ₃ , Carrie Lomelino ₃ , Jacob Andring ₃ , Laura Lucarini ₄ , Silvia Sgambellone ₄ , Emanuela Masini ₄ , Robert McKenna ₃ , Paola Gratteri _{1,

2} , Claudiu T Supuran ₁

Affiliation

The “tail approach” has become a milestone in human carbonic anhydrase inhibitor (hCAI) design for various therapeutics, including antiglaucoma agents. Besides the classical hydrophobic/hydrophilic division of hCAs active site, several subpockets have been identified at the middle/outer active sites rim, which could be targeted to increase the CAI isoform selectivity. This postulate is explored here by three-tailed benzenesulfonamide CAIs (TTI) to fully exploit such amino acid differences among hCAs. In this proof-of-concept study, an extensive structure–activity relationship (SAR) study was carried out with 32 such benzenesulfonamides differing in tails combination that were assayed for hCAs I, II, IV, and XII inhibition. A structural study was undertaken by X-ray crystallography and in silico tools to assess the ligand/target interaction mode. The most active and selective inhibitors against isoforms implicated in glaucoma were assessed in a rabbit model of the disease achieving an intraocular pressure-lowering action comparable to the clinically used dorzolamide.

中文翻译：

通过三尾法设计的人碳酸酐酶的磺酰胺抑制剂：改善配体/同工型匹配和作用选择性。

“尾巴方法”已成为人类碳酸酐酶抑制剂（hCAI）设计用于各种治疗药物（包括抗青光眼药物）的里程碑。除了hCAs活性位点的经典疏水/亲水区分开，在中间/外部活性位点边缘还发现了一些亚口袋，可以用于增加CAI同工型的选择性。三尾苯磺酰胺CAI（TTI）在这里探讨了这种假设，以充分利用hCA之间的这种氨基酸差异。在此概念验证研究中，我们对32种在尾部组合方面不同的苯磺酰胺进行了广泛的构效关系（SAR）研究，并分析了它们对hCAs I，II，IV和XII的抑制作用。通过X射线晶体学和计算机模拟进行了结构研究评估配体/靶标相互作用模式的工具。在该疾病的兔子模型中评估了与青光眼有关的同工型的最有效和选择性抑制剂，该抑制剂可实现与临床使用的多佐胺相当的眼内压降低作用。

更新日期：2020-07-09

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11