期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 15, 页码 4376-4381出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.06.082
关键词
Carbonic anhydrase; Sulfonamide; 1,3,4-Thiadiazole-2-sulfonamide; X-ray crystallography; Enzyme-inhibitor; Isoforms I-XV
资金
- European Union
- NIH [GM2515, GM25154]
- Thomas Maren grant
We investigated the inhibitory activity of several 1,3,4-thiadiazole-sulfonamides against all catalytically active CA (EC 4.2.1.1), CA I-XV. The tail derivatizing the 5-position in the 1,3,4-thiadiazole-2-sulfonamide scaffold was observed to be critical as an inhibitory determinant of these compounds. The high resolution X-ray crystal structure of hCA II in complex with 5-(1-adamantylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide, showed the adamantyl moiety of the inhibitor residing in a less utilized binding pocket than that of most hydrophobic inhibitors, lined by the amino acid residues Ile91, Val121 and Phe131. This binding site may explain the diverse inhibition profiles of 5-carboxamide- and sufonamide-derivatized 1,3,4-thiadiazole-2-sulfonamides and offers a hot spot for designing isoform selective inhibitors, considering that residues 91 and 131 are highly variable among the 13 catalytically active isoforms. (C) 2010 Elsevier Ltd. All rights reserved.
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