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

Xuehua Zheng, Liping Zhang, Jing Zhai, Yunyun Chen, Haibin Luo, Xiaopeng Hu

Index: FEBS Lett. 586(1) , 55-9, (2012)

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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.Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.