4Z0Q

Carbonic anhydrase inhibitors: Design and synthesis of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms (hCA VII, hCA IX, and hCA XIV)

4Z0Q の概要

• エントリーDOI: 10.2210/pdb4z0q/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, 4-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: carbonate dehydratase ii, carbonic anhydrase c, carbonic anhydrase ii, ca-ii, carbonate dehydratase ii- inhibitor complex, 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: 29452.57

構造登録者

Brynda, J.,Pospisilova, K.,Rezacova, P.,Pachl, P. (登録日: 2015-03-26, 公開日: 2015-08-26, 最終更新日: 2024-01-10)

主引用文献

Buemi, M.R.,De Luca, L.,Ferro, S.,Bruno, E.,Ceruso, M.,Supuran, C.T.,Pospisilova, K.,Brynda, J.,Rezacova, P.,Gitto, R.
Carbonic anhydrase inhibitors: Design, synthesis and structural characterization of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms.
Eur.J.Med.Chem., 102:223-232, 2015

PubMed Abstract: A set of heteroaryl-N-carbonylbenzenesulfonamides has been designed, synthesized, and screened as inhibitors of human carbonic anhydrases (hCAs). The new sulfonamide derivatives were tested against hCA I, hCA II, hCA VII, hCA IX, and hCA XII isoforms using acetazolamide (AAZ, 1) and topiramate (TPM, 2) as reference compounds. Six compounds were low nanomolar inhibitors of tumor-associated hCA IX isoform (Ki values < 10 nM); among them we identified three arylsulfonamides showing unexpected inefficacy over brain distributed hCA VII isoform (hCA IX/hCA VII selectivity ratio > 1500 for compound 5c). Thus, these compounds can offer the opportunity to highlight the interactions preventing the inhibition of hCA VII mainly expressed in central nervous system. Thereby, we used structural and computational techniques to study in depth the interaction with hCAs. In an effort to confirm the inhibitory action we determined crystal structures of five selected heteroaryl-N-carbonylbenzenesulfonamides (4a, 4b, 4e, 5c, and 5e) in complex with hCA II. Moreover, to explore the lack of inhibitory effects of selected compounds (e.g.4b and 5c) we also performed docking studies into hCA VII catalytic site.

PubMed: 26276436
DOI: 10.1016/j.ejmech.2015.07.049

実験手法

X-RAY DIFFRACTION (1.45 Å)