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

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4376-81. doi: 10.1016/j.bmcl.2010.06.082. Epub 2010 Jun 17.

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.

Publication types

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

MeSH terms

  • Acetazolamide / analogs & derivatives*
  • Animals
  • Binding Sites
  • Carbonic Anhydrase II / antagonists & inhibitors*
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Computer Simulation
  • Crystallography, X-Ray
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology

Substances

  • Carbonic Anhydrase Inhibitors
  • Protein Isoforms
  • Sulfonamides
  • Carbonic Anhydrase II
  • Acetazolamide

Associated data

  • PDB/3MHC