Balendu Sankara Avvaru, Jason M Wagner, Alfonso Maresca, Andrea Scozzafava, Arthur H Robbins, Claudiu T Supuran, Robert McKenna
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box Gainesville, FL 32610, USA.
Bioorganic & medicinal chemistry letters 2010 Aug 1We 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. Copyright 2010 Elsevier Ltd. All rights reserved.
Balendu Sankara Avvaru, Jason M Wagner, Alfonso Maresca, Andrea Scozzafava, Arthur H Robbins, Claudiu T Supuran, Robert McKenna. Carbonic anhydrase inhibitors. The X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors. Bioorganic & medicinal chemistry letters. 2010 Aug 1;20(15):4376-81
PMID: 20605094
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