rhodanine and zopolrestat

The antineoplastic target aldo-keto reductase family member 1B10 (AKR1B10) and the critical polyol pathway enzyme aldose reductase (AKR1B1) share high structural similarity. Crystal structures reported here reveal a surprising Trp112 native conformation stabilized by a specific Gln114-centered hydrogen bond network in the AKR1B10 holoenzyme, and suggest that AKR1B1 inhibitors could retain their binding affinities toward AKR1B10 by inducing Trp112 flip to result in an "AKR1B1-like" active site in AKR1B10, while selective AKR1B10 inhibitors can take advantage of the broader active site of AKR1B10 provided by the native Trp112 side-chain orientation.

Topics: Aldehyde Reductase; Aldo-Keto Reductases; Benzothiazoles; Catalytic Domain; Crystallography, X-Ray; Enzyme Inhibitors; Flufenamic Acid; Hydrogen Bonding; Imidazolidines; Models, Molecular; Naphthalenes; Oleanolic Acid; Phthalazines; Protein Binding; Protein Structure, Secondary; Rhodanine; Structural Homology, Protein; Thiazolidines; Tryptophan