title: Effect of incorporating a thiophene tail in the scaffold of acetazolamide on the inhibition of human carbonic anhydrase isoforms I, II, IX and XII.
abstract: The high resolution crystal structure of 5-(2-thienylacetamido)-1,3,4-thiadiazole-2-sulfonamide complexed to human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoform hCA II is reported. The compound binds in a similar manner with acetazolamide when the sulfamoyl-thiadiazolyl-acetamido fragment of the two compounds is considered, but the thienyl tail was positioned in the subpocket 2, rarely observed by other investigated CA inhibitors. This positioning allows interaction with amino acid residues (such as Asn67, Ile91, Gln92 and Val121 which are variable in other isoforms of medicinal chemistry interest, such as hCA I, IX and XII. Indeed, the investigated sulfonamide was a medium potency hCA I and II inhibitor but was highly effective as a hCA IX and XII inhibitor. This different behavior with respect to acetazolamide (a promiscuous inhibitor of all these isoforms) has been explained by resolving the crystal structure, and may be used to design more isoform-selective compounds.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
authors.forename: Shyamasri
authors.initials: S
authors.lastname: Biswas
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000086:Acetazolamide / Q000737:chemistry*; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D013876:Thiophenes; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII; D000086:Acetazolamide
keywords: Acetazolamide; Carbonic anhydrase; Isoformselective inhibitor; Thiopheneacetamide; X-ray crystallography