title: Carbonic anhydrase inhibitors. Interaction of the antiepileptic drug sulthiame with twelve mammalian isoforms: kinetic and X-ray crystallographic studies.
abstract: Sulthiame, a clinically used antiepileptic, was investigated for its interaction with 12 catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms. The drug is a potent inhibitor of CA II, VII, IX, and XII (K(I)s of 6-56 nM), and a medium potency inhibitor against CA IV, VA, VB, and VI (K(I)s of 81-134 nM). The high resolution crystal structure of the hCA II-sulthiame adduct revealed a large number of favorable interactions between the drug and the enzyme which explain its strong low nanomolar affinity for this isoform and may also be exploited for the design of effective inhibitors incorporating sultam moieties.
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Temperini
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Antonio
authors.initials: A
authors.lastname: Mastrolorenzo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004583:Electrons; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D020033:Protein Isoforms; D013843:Thiazines / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000927:Anticonvulsants; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D020033:Protein Isoforms; D013843:Thiazines; C084593:sulthiame; D000096926:Benzenesulfonamides