Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action.
Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action.
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DOI：
10.1021/acs.jmedchem.0c00733
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发表时间：
2020-07-09
影响因子：
7.3
通讯作者：
Supuran CT
中科院分区：
文献类型：
--
作者：
Bonardi A;Nocentini A;Bua S;Combs J;Lomelino C;Andring J;Lucarini L;Sgambellone S;Masini E;McKenna R;Gratteri P;Supuran CT
“尾部方法”已成为人类碳酸酐酶抑制剂（hCAI）设计的里程碑，用于各种治疗，包括抗青光眼药物。除了hCA活性位点的经典疏水/亲水划分之外，已经在中间/外部活性位点边缘鉴定了几个亚袋，其可以被靶向以增加CAI异构体选择性。在此通过三尾苯磺酰胺CAIs（TTI）探索该假设，以充分利用hCA之间的这种氨基酸差异。在该概念验证研究中，使用32种尾部组合不同的苯磺酰胺进行了广泛的结构-活性关系（SAR）研究，测定了hCA I、II、IV和XII抑制。通过X射线晶体学和计算机工具进行结构研究，以评估配体/靶相互作用模式。在兔青光眼模型中评估了对青光眼相关亚型最具活性和选择性的抑制剂，其降低眼内压的作用与临床使用的多佐胺相当。
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.
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人类碳赤霉素II的活性位点中的短而强的氢键。
影响因子：
2.9
作者：
Avvaru, Balendu Sankara;Kim, Chae Un;Sippel, Katherine H.;Gruner, Sol M.;Agbandje-McKenna, Mavis;Silverman, David N.;McKenna, Robert
通讯作者：
McKenna, Robert
影响因子：
3
作者：
De Simone, Giuseppina;Scozzafava, Andrea;Supuran, Claudiu T.
通讯作者：
Supuran, Claudiu T.
DOI：
10.1016/j.bbapap.2009.08.026
发表时间：
2010-02
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Ferry JG
通讯作者：
Ferry JG
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.9
作者：
Fisher, S. Zoe;Kovalevsky, Andrey Y.;Langan, Paul A.
通讯作者：
Langan, Paul A.