The structure of human recombinant aldose reductase complexed with the potent inhibitor zenarestat

Abstract

The crystal structure of the complex of human recombinant aldose reductase (AR) with zenarestat, one of its potent inhibitors, has been solved at 2.5 A resolution. Zenarestat fits neatly in the hydrophobic active site and induces unique and dramatic conformational changes. For example, the benzene ring of zenarestat occupies a gap in the side chains of Leu300 and Trp111 that interact directly and forms a CH-pi interaction in the native holoenzyme. As a result, the benzene ring of the inhibitor and these side chains form a CH-pi-pi interaction. Such structural information is key to understanding the mode of action of this class of inhibitors and for rational design of better therapeutics.

Novel Aldose Reductase Inhibitors Derived from 6‐[[(Diphenylmethylene)amino]oxy]hexanoic Acid

“…According to the in vitro results obtained for compounds 15 -24 (see Table 1), it was found that the 2-substituted congeners are less active, e. g. IC 50 16.5 lM (16) vs. 4.80 lM (19). Concerning the nature of the alkoxy substituent, nearly the same activities were obtained for 15 -18, by contrast, within the series of 4,49-disubstituted compounds, derivatives bearing propoxy (20) or butoxy (21), respectively, are less active. However, congeners 22 -24 bearing disubstituted phenyl rings exhibit the highest activities (IC 50 L 3 lM) which lie almost in the same range of the reference sorbinil (IC 50 L 1.2 lM).…”

Evidence for a Novel Binding Site Conformer of Aldose Reductase in Ligand-Bound State

“…7 With slight additional adaptations, in particular with respect to the orientation of the Ala 299-Leu 300 peptide region, the latter is the most frequently observed pocket conformer, e.g. also addressed by the ligands zopolrestat, 20,21 minalrestat, 22 zenarestat, 23 IDD 552, 24 and a recently published sulfonylpyridazinone inhibitor. 10 The novel series of naphtho [1,2-d]isothiazole acetic acid derivatives was designed with the idea of freezing the bound conformation of tolrestat by introducing a sulfolactam ring.…”

Experimental validation and docking studies of flavone derivatives on aldose reductase involved in diabetic retinopathy, neuropathy, and nephropathy

“…Studies also show that the side chain of Leu300 makes a direct contact with the aromatic ring of Trp111 in the native human holoenzyme (PDB code: 1ADS). These hydrophobic interactions are further stabilized by the phenyl ring of Phe-122 whose edge contacts halogenated phenyl ring which are similar to that described for the larger benzothiazole ring of zopolrestat and zenarestat (Kinoshita et al, 2002). The oxygen atom allows a nearly orthogonal orientation of the side chain phenyl ring such that the electronegative chlorine atom in the second phenyl ring makes contact with both Trp-20 and the pyridinium group of NADP ?…”