Carbonic anhydrase inhibitors: clash with Ala65 as a means for designing inhibitors with low affinity for the ubiquitous isozyme II, exemplified by the crystal structure of the topiramate sulfamide analogue

J Med Chem. 2006 Nov 30;49(24):7024-31. doi: 10.1021/jm060807n.

Abstract

The sulfamide analogue of the antiepileptic drug topiramate is a 210 times less potent inhibitor of isozyme II of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) compared to topiramate but effectively inhibits isozymes CA VA, VB, VII, XIII, and XIV (KI in the range of 21-35 nM). Its weak binding to CA II is due to a clash between one methyl group of the inhibitor and Ala65 and may be exploited for the drug design of compounds with lower affinity for this ubiquitous isozyme, as Ala65 is unique to CA II. As shown by X-ray crystallography, the sulfamide analogue binds to CA II with the deprotonated sulfamide moiety coordinated to Zn(II) and with the organic scaffold making an extended network of hydrogen bonds with Thr199, Gln92, His94, Asn62, and Thr200. Its binding to this isozyme is more similar to that of topiramate and quite different from that of the topiramate cyclic sulfate analogue RWJ-37947.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / chemistry*
  • Anticonvulsants / chemistry
  • Carbonic Anhydrase II / chemistry*
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Crystallography, X-Ray
  • Drug Design
  • Fructose / analogs & derivatives*
  • Fructose / chemical synthesis
  • Fructose / chemistry
  • Hydrogen Bonding
  • Isoenzymes / chemistry
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Topiramate

Substances

  • Anticonvulsants
  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides
  • Topiramate
  • Fructose
  • Carbonic Anhydrase II
  • Alanine

Associated data

  • PDB/2H15