5N0E

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

Summary for 5N0E

• Entry DOI: 10.2210/pdb5n0e/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, 4-[[(1~{S})-6,7-bis(oxidanyl)-1-phenyl-3,4-dihydro-1~{H}-isoquinolin-2-yl]carbonyl]benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: human carbonic anhydrase, benzesulfonamide, protein-inhibitor adduct, lyase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29967.19

Authors

Di Fiore, A.,De Simone, G. (deposition date: 2017-02-02, release date: 2017-05-10, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.75 Å)