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.
Xuehua Zheng  1 ,  Liping Zhang ,  Jing Zhai ,  Yunyun Chen ,  Haibin Luo ,  Xiaopeng Hu
Affiliations
  • 1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. [email protected]
PMID: 22155003 DOI: 10.1016/j.febslet.2011.11.023
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.

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