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舒林酸及其代谢物抑制人醛糖还原酶的分子基础。

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

机构信息

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

出版信息

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

DOI:10.1016/j.febslet.2011.11.023
PMID:22155003
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.

摘要

舒林酸（SLD）在常用的非甾体抗炎药中对人醛糖还原酶（AR）具有最高的抑制活性，并且对 2 型糖尿病具有明显的临床疗效。但是，这些特性的分子基础尚不清楚。在这里，我们报告 SLD 及其药理活性/无活性代谢物，SLD 硫化物和 SLD 砜，在体外均是 AR 的非竞争性抑制剂。晶体学分析表明，SLD 独特骨架所支持的π-π堆积对其高 AR 抑制活性至关重要。这些结果还表明，SLD 砜可能是体内 AR 抑制的潜在有效先导化合物。

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