Saccharin: a lead compound for structure-based drug design of carbonic anhydrase IX inhibitors

Bioorg Med Chem. 2015 Feb 15;23(4):849-54. doi: 10.1016/j.bmc.2014.12.030. Epub 2014 Dec 23.

Abstract

Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (>50-fold for SAC and >1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are presented and compared to CA II. The structures provide substantial new insight into the mechanism of SAC selective CA isoform inhibition.

Keywords: CA IX-mimic; Carbonic anhydrase IX; Metalloenzyme; Saccharin; Structure-based drug design.

Publication types

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

MeSH terms

  • Antigens, Neoplasm / chemistry
  • Antigens, Neoplasm / metabolism*
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / chemistry
  • Carbonic Anhydrases / metabolism*
  • Crystallography, X-Ray
  • Drug Design*
  • Humans
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Saccharin / chemistry*
  • Saccharin / pharmacology*

Substances

  • Antigens, Neoplasm
  • Carbonic Anhydrase Inhibitors
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • Saccharin