5N0D

Crystal structure of human carbonic anhydrase II in complex with (R)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1H-2-carbonyl)benzenesulfonamide.

5N0D の概要

• エントリーDOI: 10.2210/pdb5n0d/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, (R)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1H-2-carbonyl)benzenesulfonamide, ... (5 entities in total)
• 機能のキーワード: carbonic anhydrase, benzesulfonamide, protein-inhibitor adduct, 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: 30059.28

構造登録者

Di Fiore, A.,De Simone, G. (登録日: 2017-02-02, 公開日: 2017-05-10, 最終更新日: 2024-01-17)

主引用文献

Bruno, E.,Buemi, M.R.,Di Fiore, A.,De Luca, L.,Ferro, S.,Angeli, A.,Cirilli, R.,Sadutto, D.,Alterio, V.,Monti, S.M.,Supuran, C.T.,De Simone, G.,Gitto, R.
Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides.
J. Med. Chem., 60:4316-4326, 2017

PubMed Abstract: On the basis of X-ray crystallographic studies of the complex of hCA II with 4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)benzenesulfonamide (3) (PDB code 4Z1J ), a novel series of 4-(1-aryl-3,4-dihydro-1H-isoquinolin-2-carbonyl)benzenesulfonamides (23-33) was designed. Specifically, our idea was to improve the selectivity toward druggable isoforms through the introduction of additional hydrophobic/hydrophilic functionalities. Among the synthesized and tested compounds, the (R,S)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1H-2-carbonyl)benzenesulfonamide (30) exhibited a remarkable inhibition for the brain-expressed hCA VII (K = 0.20 nM) and selectivity over wider distributed hCA I and hCA II isoforms. By enantioselective HPLC, we solved the racemic mixture and ascertained that the two enantiomers (30a and 30b) are equiactive inhibitors for hCA VII. Crystallographic and docking studies revealed the main interactions of these inhibitors into the carbonic anhydrase (CA) catalytic site, thus highlighting the relevant role of nonpolar contacts for this class of hCA inhibitors.

PubMed: 28453941
DOI: 10.1021/acs.jmedchem.7b00264

実験手法

X-RAY DIFFRACTION (1.7 Å)