title: Carbonic anhydrase inhibitors: X-ray crystallographic studies for the binding of 5-amino-1,3,4-thiadiazole-2-sulfonamide and 5-(4-amino-3-chloro-5-fluorophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide to human isoform II.
abstract: The X-ray crystal structures of 5-amino-1,3,4-thiadiazole-2-sulfonamide (the acetazolamide precursor) and 5-(4-amino-3-chloro-5-fluorophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide in complex with the human isozyme II of carbonic anhydrase (CA, EC 4.2.1.1) are reported. The thiadiazole-sulfonamide moiety of the two compounds binds in the canonic manner to the zinc ion and interacts with Thr199, Glu106, and Thr200. The substituted phenyl tail of the second inhibitor was positioned in the hydrophobic part of the binding pocket, at van der Waals distance from Phe131, Val 135, Val141, Leu198, Pro202, and Leu204. These structures may help in the design of better inhibitors of these widespread zinc-containing enzymes.
authors.affiliation: Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Menchise
authors.forename: Giuseppina
authors.initials: G
authors.lastname: De Simone
authors.forename: Anna
authors.initials: A
authors.lastname: Di Fiore
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D002256:Carbonic Anhydrases / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics*; D013830:Thiadiazoles / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C517142:5-(4-amino-3-chloro-5-fluorophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide; D002257:Carbonic Anhydrase Inhibitors; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013830:Thiadiazoles; D002256:Carbonic Anhydrases