4BF1

Three dimensional structure of human carbonic anhydrase II in complex with 5-(1-naphthalen-1-yl-1,2,3-triazol-4-yl)thiophene-2-sulfonamide

4BF1 の概要

• エントリーDOI: 10.2210/pdb4bf1/pdb
• 関連するPDBエントリー: 4BF6
• 分子名称: CARBONIC ANHYDRASE 2, ZINC ION, 5-(1-naphthalen-1-yl-1,2,3-triazol-4-yl)thiophene-2-sulfonamide, ... (5 entities in total)
• 機能のキーワード: lyase
• 由来する生物種: HOMO SAPIENS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29602.68

構造登録者

Tars, K.,Leitans, J.,Zalubovskis, R. (登録日: 2013-03-13, 公開日: 2014-01-22, 最終更新日: 2023-12-20)

主引用文献

Leitans, J.,Sprudza, A.,Tanc, M.,Vozny, I.,Zalubovskis, R.,Tars, K.,Supuran, C.T.
5-Substituted-(1,2,3-Triazol-4-Yl)Thiophene-2-Sulfonamides Strongly Inhibit Human Carbonic Anhydrases I, II, Ix and Xii: Solution and X-Ray Crystallographic Studies.
Bioorg.Med.Chem., 21:5130-, 2013

PubMed Abstract: We report here a series of 2-thiophene-sulfonamides incorporating 1-substituted aryl-1,2,3-triazolyl moieties, prepared by click chemistry from 5-ethynylthiophene-2-sulfonamide and substituted aryl azides. The new sulfonamides were investigated as inhibitors of the zinc metalloenzyme CA (EC 4.2.1.1), and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated ones hCA IX and XII: The new compounds were medium-weak hCA I inhibitors (KIs in the range of 224-7544nM), but were compactly, highly effective, low nanomolar hCA II inhibitors (KIs of 2.2-7.7nM). The tumor-associated hCA IX was inhibited with KIs ranging between 5.4 and 811nM, whereas hCA XII with inhibition constants in the range of 3.4-239nM. The X-ray crystal structure of the adducts of two such compounds bound to hCA II (one incorporating 1-naphthyl, the other one 3-cyanophenyl moieties) evidenced the reasons of the high affinity for hCA II. Highly favorable, predominantly hydrophobic interactions between the sulfonamide scaffold and the hCA II active site were responsible for the binding, in addition to the coordination of the sulfamoyl moiety to the zinc ion. The tails of the two inhibitors adopted very diverse orientations when bound to the active site, with the naphthyltriazolyl moiety orientated towards the hydrophobic half of the active site, and the 3-cyanophenyl one pointing towards the hydrophilic half. These data may be used for the structure-based drug design of even more effective hCA II inhibitors, with potential use as antiglaucoma agents or as diuretics.

PubMed: 23859774
DOI: 10.1016/J.BMC.2013.06.041

実験手法

X-RAY DIFFRACTION (1.35 Å)