title: Inhibition of mammalian carbonic anhydrases I-XIV with grayanotoxin III: solution and in silico studies.
abstract: Grayanotoxin III (GTX3) was investigated for inhibition of all catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms, i.e. CA I to CA XIV. It showed micromolar inhibition (KIs of 8.01 and 6.13 µM) for cytosolic isoforms CA I and II, respectively. GTX3 showed a submicromolar inhibition (KIs in the range of 0.51-2.15 µM) for the remaining cytosolic (CA III, VII and XIII), membrane-associated/transmembrane (CA IV, IX, XII and XIV), mitochondrial (CA VA and CA VB) and secreted (CA VI) isoforms. This inhibition profile is very different from that of the sulfonamide CA inhibitors (CAIs), which possess different clinical applications. A molecular docking study for GTX3 within the active sites of CA I and II assisted to the understanding of molecular mechanism of the ligand. The interesting inhibition profile, coupled with various possibilities of interacting with the enzyme active site make this family of natural compounds attractive leads for designing novel chemotypes acting as CAIs.
authors.affiliation: University of Calgary, Institute for Biocomplexity and Informatics , Calgary, AB , Canada .
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Scozzafava
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Sahin
authors.forename: Sevgi
authors.initials: S
authors.lastname: Kolayli
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D003198:Computer Simulation; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D004224:Diterpenes; D007527:Isoenzymes; D012996:Solutions; D002256:Carbonic Anhydrases; C020751:grayanotoxin III
keywords: Carbonic anhydrase; grayanotoxin III; molecular docking