title: The molecular basis for inhibition of sulindac and its metabolites towards human aldose reductase.
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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. huxpeng@mail.sysu.edu.cn
authors.forename: Xuehua
authors.initials: X
authors.lastname: Zheng
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhai
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Chen
authors.forename: Haibin
authors.initials: H
authors.lastname: Luo
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Hu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D011487:Protein Conformation; D013467:Sulindac / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D013467:Sulindac; C025462:sulindac sulfide; D000449:Aldehyde Reductase; C025463:sulindac sulfone