The molecular basis for inhibition of sulindac and its metabolites towards human aldose reductase

FEBS Lett. 2012 Jan 2;586(1):55-9. doi: 10.1016/j.febslet.2011.11.023. Epub 2011 Dec 8.

Abstract

Sulindac (SLD) exhibits both the highest inhibitory activity towards human aldose reductase (AR) among popular non-steroidal anti-inflammatory drugs and clear beneficial clinical effects on Type 2 diabetes. However, the molecular basis for these properties is unclear. Here, we report that SLD and its pharmacologically active/inactive metabolites, SLD sulfide and SLD sulfone, are equally effective as un-competitive inhibitors of AR in vitro. Crystallographic analysis reveals that π-π stacking favored by the distinct scaffold of SLDs is pivotal to their high AR inhibitory activities. These results also suggest that SLD sulfone could be a potent lead compound for AR inhibition in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Reductase / antagonists & inhibitors*
  • Aldehyde Reductase / chemistry*
  • Aldehyde Reductase / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Crystallography, X-Ray
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Protein Conformation
  • Sulindac / analogs & derivatives
  • Sulindac / chemistry
  • Sulindac / metabolism
  • Sulindac / pharmacology*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Sulindac
  • sulindac sulfide
  • Aldehyde Reductase
  • sulindac sulfone

Associated data

  • PDB/3RX2
  • PDB/3RX3
  • PDB/3RX4