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.
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.
Di Fiore
Anna
A
Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Napoli, Italy.
Pedone
Carlo
C
Antel
Jochen
J
Waldeck
Harald
H
Witte
Andreas
A
Wurl
Michael
M
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
De Simone
Giuseppina
G
D000818:Animals; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002384:Catalysis; D018360:Crystallography, X-Ray; D005016:Ethoxzolamide / Q000737:chemistry* / Q000494:pharmacology; D005973:Glutamine / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013912:Threonine / Q000737:chemistry
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D005973:Glutamine; D013912:Threonine; D024402:Carbonic Anhydrase II; D005016:Ethoxzolamide