2H15

Carbonic anhydrase inhibitors: Clashing with Ala65 as a means of designing isozyme-selective inhibitors that show low affinity for the ubiquitous isozyme II

2H15 の概要

• エントリーDOI: 10.2210/pdb2h15/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, MERCURY (II) ION, ... (5 entities in total)
• 機能のキーワード: carbonic anhydrase, inhibitors, lyase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : P00918
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29893.44

構造登録者

Winum, J.Y.,Temperini, C.,Ciattini, S.,Scozzafava, A.,Supuran, C.T. (登録日: 2006-05-16, 公開日: 2007-03-27, 最終更新日: 2024-02-14)

主引用文献

Winum, J.Y.,Temperini, C.,El Cheikh, K.,Innocenti, A.,Vullo, D.,Ciattini, S.,Montero, J.L.,Scozzafava, A.,Supuran, C.T.
Carbonic anhydrase inhibitors: clash with Ala65 as a means for designing inhibitors with low affinity for the ubiquitous isozyme II, exemplified by the crystal structure of the topiramate sulfamide analogue.
J.Med.Chem., 49:7024-7031, 2006

PubMed Abstract: The sulfamide analogue of the antiepileptic drug topiramate is a 210 times less potent inhibitor of isozyme II of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) compared to topiramate but effectively inhibits isozymes CA VA, VB, VII, XIII, and XIV (KI in the range of 21-35 nM). Its weak binding to CA II is due to a clash between one methyl group of the inhibitor and Ala65 and may be exploited for the drug design of compounds with lower affinity for this ubiquitous isozyme, as Ala65 is unique to CA II. As shown by X-ray crystallography, the sulfamide analogue binds to CA II with the deprotonated sulfamide moiety coordinated to Zn(II) and with the organic scaffold making an extended network of hydrogen bonds with Thr199, Gln92, His94, Asn62, and Thr200. Its binding to this isozyme is more similar to that of topiramate and quite different from that of the topiramate cyclic sulfate analogue RWJ-37947.

PubMed: 17125255
DOI: 10.1021/jm060807n

実験手法

X-RAY DIFFRACTION (1.9 Å)