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

Zheng, Xuehua; Zhang, Liping; Zhai, Jing; Chen, Yunyun; Luo, Hai‐Bin; Hu, Xiaopeng

doi:10.1016/j.febslet.2011.11.023

Cited by 37 publications

(21 citation statements)

References 35 publications

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“…Such screening is unavoidable as a preliminary step before an in depth kinetic analysis of the selected molecules, and is usually performed at rather high GAL concentrations [59-62]. This leads to an underestimation of the effectiveness of molecules which display a competitive or mixed noncompetitive type of inhibition, especially, in the latter case, when the component of the competitive action is dominant.…”

Section: Resultsmentioning

confidence: 99%

A New Approach to Control the Enigmatic Activity of Aldose Reductase

et al. 2013

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Aldose reductase (AR) is an NADPH-dependent reductase, which acts on a variety of hydrophilic as well as hydrophobic aldehydes. It is currently defined as the first enzyme in the so-called polyol pathway, in which glucose is transformed into sorbitol by AR and then to fructose by an NAD+-dependent dehydrogenase. An exaggerated flux of glucose through the polyol pathway (as can occur in diabetes) with the subsequent accumulation of sorbitol, was originally proposed as the basic event in the aethiology of secondary diabetic complications. For decades this has meant targeting the enzyme for a specific and strong inhibition. However, the ability of AR to reduce toxic alkenals and alkanals, which are products of oxidative stress, poses the question of whether AR might be better classified as a detoxifying enzyme, thus raising doubts as to the unequivocal advantages of inhibiting the enzyme. This paper provides evidence of the possibility for an effective intervention on AR activity through an intra-site differential inhibition. Examples of a new generation of aldose reductase “differential” inhibitors (ARDIs) are presented, which can preferentially inhibit the reduction of either hydrophilic or hydrophobic substrates. Some selected inhibitors are shown to preferentially inhibit enzyme activity on glucose or glyceraldehyde and 3-glutathionyl-4-hydroxy-nonanal, but are less effective in reducing 4-hydroxy-2-nonenal. We question the efficacy of D, L-glyceraldehyde, the substrate commonly used in in vitro inhibition AR studies, as an in vitro reference AR substrate when the aim of the investigation is to impair glucose reduction.

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Section: Resultsmentioning

confidence: 99%

A New Approach to Control the Enigmatic Activity of Aldose Reductase

et al. 2013

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“…AKR1B10‐NADP + –inhibitor ternary complex crystals were prepared by co‐crystallization. The crystal of the AKR1B1‐NADP + –epalrestat ternary complex was prepared as described previously [15]. X‐ray diffraction data were collected at 100 K on an in‐house Oxford Diffraction Xcalibur Nova diffractometer.…”

Section: Methodsmentioning

confidence: 99%

Inhibitor selectivity between aldo–keto reductase superfamily members AKR1B10 and AKR1B1: Role of Trp112 (Trp111)

Zhang

Zhao

et al. 2013

FEBS Letters

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a b s t r a c tThe 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.

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“…66 the way the other negatively charged aldose reductase inhibitors do (Bohren and Grimshaw 2000). Uncompetitive type of inhibition was proved for another indole-1-acetic acid derivative, sulindac (Zheng et al 2012).…”

Section: Discussionmentioning

confidence: 97%

Does Inhibition of Aldose Reductase Contribute to the Anti-Inflammatory Action of Setipiprant?

Ballekova¹,

Soltesova-Prnova²,

Májeková³

et al. 2017

Physiol Res

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The aim of this study was to investigate aldose reductase inhibitory action of setipiprant as a potential additional mechanism contributing to its anti-inflammatory action. Aldose reductase activity was determined by spectrophotometric measuring of NADPH consumption. Setipiprant was found to inhibit aldose reductase/NADPH-mediated reduction of 4-hydroxynonenal, 4-hydroxynonenal glutathione and prostaglandin H2 substrates, all relevant to the process of inflammation. Molecular modeling simulations into the aldose reductase inhibitor binding site revealed an interaction pattern of setipiprant. Considering multifactorial etiology of inflammatory pathologies, it is suggested that, in addition to the antagonizing prostaglandin D2 receptor, inhibition of aldose reductase may contribute to the reported anti-inflammatory action of setipiprant.

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

Cited by 37 publications

References 35 publications

A New Approach to Control the Enigmatic Activity of Aldose Reductase

A New Approach to Control the Enigmatic Activity of Aldose Reductase

Inhibitor selectivity between aldo–keto reductase superfamily members AKR1B10 and AKR1B1: Role of Trp112 (Trp111)

Does Inhibition of Aldose Reductase Contribute to the Anti-Inflammatory Action of Setipiprant?

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