Carbonic anhydrase inhibitors. the X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors

Balendu Sankara Avvaru, Jason M. Wagner, Alfonso Maresca, Andrea Scozzafava, Arthur H. Robbins, Claudiu T. Supuran, Robert McKenna

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

We investigated the inhibitory activity of several 1,3,4-thiadiazole- sulfonamides against all catalytically active CA (EC 4.2.1.1), CA I-XV. The tail derivatizing the 5-position in the 1,3,4-thiadiazole-2-sulfonamide scaffold was observed to be critical as an inhibitory determinant of these compounds. The high resolution X-ray crystal structure of hCA II in complex with 5-(1-adamantylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide, showed the adamantyl moiety of the inhibitor residing in a less utilized binding pocket than that of most hydrophobic inhibitors, lined by the amino acid residues Ile91, Val121 and Phe131. This binding site may explain the diverse inhibition profiles of 5-carboxamide- and sufonamide-derivatized 1,3,4-thiadiazole-2-sulfonamides and offers a hot spot for designing isoform selective inhibitors, considering that residues 91 and 131 are highly variable among the 13 catalytically active isoforms.

Original languageEnglish (US)
Pages (from-to)4376-4381
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number15
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

Keywords

  • 1,3,4-Thiadiazole-2-sulfonamide
  • Carbonic anhydrase
  • Enzyme-inhibitor
  • Isoforms I-XV
  • Sulfonamide
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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