Carbonic anhydrase inhibitors: The X-ray crystal structure of ethoxzolamide complexed to human isoform II reveals the importance of thr200 and gln92 for obtaining tight-binding inhibitors

An X-ray crystallographic study for the binding of ethoxzolamide to human carbonic anhydrase (CA) II provides useful insights for the design of novel CA inhibitors targeting different isozymes. Ethoxzolamide, an almost forgotten inhibitor of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), is...

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Veröffentlicht in:Bioorganic & medicinal chemistry 2008-04, Vol.18 (8), p.2669-2674
Hauptverfasser: Di Fiore, Anna, Pedone, Carlo, Antel, Jochen, Waldeck, Harald, Witte, Andreas, Wurl, Michael, Scozzafava, Andrea, Supuran, Claudiu T., De Simone, Giuseppina
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container_end_page 2674
container_issue 8
container_start_page 2669
container_title Bioorganic & medicinal chemistry
container_volume 18
creator Di Fiore, Anna
Pedone, Carlo
Antel, Jochen
Waldeck, Harald
Witte, Andreas
Wurl, Michael
Scozzafava, Andrea
Supuran, Claudiu T.
De Simone, Giuseppina
description An X-ray crystallographic study for the binding of ethoxzolamide to human carbonic anhydrase (CA) II provides useful insights for the design of novel CA inhibitors targeting different isozymes. Ethoxzolamide, an almost forgotten inhibitor of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), is the only classical inhibitor whose structure in adduct with any isoform was not reported yet. We report here the inhibition data of this molecule with the 12 catalytically active mammalian isozymes (CA I–CA XIV) and the X-ray crystal structure with the cytosolic, ubiquitous isoform CA II. These data are presumably useful for the design of novel CA inhibitors, targeting various CA isozymes, considering that ethoxzolamide was already the lead molecule to obtain the second generation inhibitors, dorzolamide and brinzolamide, clinically used antiglaucoma agents with topical action, as well as various other investigational agents.
doi_str_mv 10.1016/j.bmcl.2008.03.023
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identifier ISSN: 0960-894X
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subjects Animals
Binding Sites
Biological and medical sciences
Carbonic Anhydrase
Carbonic Anhydrase II - chemistry
Carbonic Anhydrase II - metabolism
Carbonic Anhydrase Inhibitors - chemistry
Carbonic Anhydrase Inhibitors - pharmacology
Catalysis
Crystallography, X-Ray
Ethoxzolamide
Ethoxzolamide - chemistry
Ethoxzolamide - pharmacology
Eye
Glutamine - chemistry
Humans
Isoenzymes - antagonists & inhibitors
Isoenzymes - chemistry
Isoenzymes - metabolism
Medical sciences
Mice
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Protein Binding
Protein crystallography
Threonine - chemistry
title Carbonic anhydrase inhibitors: The X-ray crystal structure of ethoxzolamide complexed to human isoform II reveals the importance of thr200 and gln92 for obtaining tight-binding inhibitors
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