title: Design of [(2-pyrimidinylthio)acetyl]benzenesulfonamides as inhibitors of human carbonic anhydrases.
abstract: A series of [(2-pyrimidinylthio)acetyl]benzenesulfonamides were designed and synthesized. Their binding affinities as inhibitors of several recombinant human carbonic anhydrase (CA) isozymes were determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). A group of compounds containing a chlorine atom in the benzenesulfonamide ring were found to exhibit higher selectivity but lower binding affinity toward tested CAs. The crystal structures of selected compounds in complex with CA II were determined to atomic resolution. Docking studies were performed to compare the binding modes of experimentally determined crystallographic structures with computational prediction of the pyrimidine derivative binding to CA II. Several compounds bound to select CAs with single-digit nanomolar affinities and could be used as leads for inhibitor development toward a select CA isozyme.
authors.affiliation: Vilnius University, Institute of Biotechnology, Department of Biothermodynamics and Drug Design, Graičiūno 8, Vilnius LT-02241, Lithuania.
authors.forename: Edita
authors.initials: E
authors.lastname: Čapkauskaitė
authors.forename: Asta
authors.initials: A
authors.lastname: Zubrienė
authors.forename: Lina
authors.initials: L
authors.lastname: Baranauskienė
authors.forename: Giedrė
authors.initials: G
authors.lastname: Tamulaitienė
authors.forename: Elena
authors.initials: E
authors.lastname: Manakova
authors.forename: Visvaldas
authors.initials: V
authors.lastname: Kairys
authors.forename: Saulius
authors.initials: S
authors.lastname: Gražulis
authors.forename: Sigitas
authors.initials: S
authors.lastname: Tumkevičius
authors.forename: Daumantas
authors.initials: D
authors.lastname: Matulis
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D013449:Sulfonamides; D000096926:Benzenesulfonamides