Effect of incorporating a thiophene tail in the scaffold of acetazolamide on the inhibition of human carbonic anhydrase isoforms I, II, IX and XII.
Bioorg Med Chem Lett. 2013 Oct 15; 23(20):5646-9.BM

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.

Links

Publisher Full Text

Authors+Show Affiliations

Biswas S
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
McKenna R
No affiliation info available
Supuran CT
No affiliation info available

MeSH

AcetazolamideAntigens, NeoplasmBinding SitesCarbonic Anhydrase ICarbonic Anhydrase IICarbonic Anhydrase IXCarbonic Anhydrase InhibitorsCarbonic AnhydrasesCatalytic DomainCrystallography, X-RayHumansMolecular ConformationMolecular Docking SimulationThiophenes

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23993330