4RFC

Human carbonic anhydrase II in complex with tert-butyl 4-(4-sulfamoylphenoxy)butylcarbamate

Summary for 4RFC

• Entry DOI: 10.2210/pdb4rfc/pdb
• Related: 4RFD
• Descriptor: Carbonic anhydrase 2, ZINC ION, tert-butyl 4-(4-sulfamoylphenoxy)butylcarbamate, ... (4 entities in total)
• Functional Keywords: sulfonamide, carbonic anhydrase, antiglaucoma, o-(-aminoalkyl)-benzenesulfonamides, lyase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29698.90

Authors

Bozdag, M.,Pinard, M.A.,Carta, F.,Masini, E.,Scozzafava, A.,Mckenna, R.,Supuran, C.T. (deposition date: 2014-09-25, release date: 2015-04-15, Last modification date: 2024-02-28)

Primary citation

Bozdag, M.,Pinard, M.,Carta, F.,Masini, E.,Scozzafava, A.,McKenna, R.,Supuran, C.T.
A class of 4-sulfamoylphenyl-omega-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects.
J.Med.Chem., 57:9673-9686, 2014

PubMed Abstract: We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure-activity relationship was drawn for the inhibition of four physiologically relevant isoforms: hCA I, II, IX, and XII. Many of these compounds were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiologically dominant CA II isoform showed the tails of these derivatives bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-soluble compound (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a-c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-associated isoforms CA IX and XII.

PubMed: 25358036
DOI: 10.1021/jm501497m

Experimental method

X-RAY DIFFRACTION (1.645 Å)