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

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.

► Sulindac and its two metabolites equally inhibit aldose reductase in vitro.
► Crystal structures of sulindacs and tolmetin in complex with aldose reductase.
► Sulindac and its two metabolites have the same binding modes with aldose reductase.
► π–π Stacking favored by sulindac and Phe122 is pivotal to its high inhibition.