Identification of an aldose reductase inhibitor site by affinity labeling

Peter F. Kador, Yong S. Lee, Libaniel Rodriguez, Sanai Sato, Anita Bartoszko-Malik, Yasser S. Abdel-Ghany, Duane Miller

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Animal studies indicate that aldose reductase inhibitors represent a pharmacological method for inhibiting the onset of diabetic complications that is independent of blood sugar control. This has spurred the development of aldose reductase inhibitors (ARIs). To facilitate the rational development of more potent and direct ARIs, more specific knowledge of the structural and pharmacophoric requirements of the site at which ARIs interact are required. Co-crystallization of human placental aldose reductase with the inhibitor zopolrestat has been reported to result in a complex where the inhibitor is almost completely sequestered in the hydrophobic pocket which forms the substrate site. Zopolrestat's observed location, which makes the active site pocket inaccessible to solvent or further productive binding of substrate, is not supported by published inhibitor structure-activity relationships (SAR) studies or kinetic results which indicate that aldose reductase inhibitors such as zopolrestat are either non-competitive or uncompetitive inhibitors. Using a 5-iodoacetamido analog of alrestatin as an affinity labeled aldose reductase inhibitor, an inhibitor binding site on aldose reductase has been located. This inhibitor binding site contains a number of pharmacophoric elements previously proposed for the inhibitor site. Its location and composition is consistent with reported kinetic data, SAR observations, stereochemical requirements, and quantum chemical calculations.

Original languageEnglish (US)
Pages (from-to)1313-1324
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume3
Issue number10
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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Aldehyde Reductase
Labeling
Structure-Activity Relationship
Binding Sites
Kinetics
Substrates
Diabetes Complications
Crystallization
Data structures
Blood Glucose
Catalytic Domain
Animals
Pharmacology

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Kador, P. F., Lee, Y. S., Rodriguez, L., Sato, S., Bartoszko-Malik, A., Abdel-Ghany, Y. S., & Miller, D. (1995). Identification of an aldose reductase inhibitor site by affinity labeling. Bioorganic and Medicinal Chemistry, 3(10), 1313-1324. https://doi.org/10.1016/0968-0896(95)00118-Z

Identification of an aldose reductase inhibitor site by affinity labeling. / Kador, Peter F.; Lee, Yong S.; Rodriguez, Libaniel; Sato, Sanai; Bartoszko-Malik, Anita; Abdel-Ghany, Yasser S.; Miller, Duane.

In: Bioorganic and Medicinal Chemistry, Vol. 3, No. 10, 01.01.1995, p. 1313-1324.

Research output: Contribution to journalArticle

Kador, PF, Lee, YS, Rodriguez, L, Sato, S, Bartoszko-Malik, A, Abdel-Ghany, YS & Miller, D 1995, 'Identification of an aldose reductase inhibitor site by affinity labeling', Bioorganic and Medicinal Chemistry, vol. 3, no. 10, pp. 1313-1324. https://doi.org/10.1016/0968-0896(95)00118-Z
Kador PF, Lee YS, Rodriguez L, Sato S, Bartoszko-Malik A, Abdel-Ghany YS et al. Identification of an aldose reductase inhibitor site by affinity labeling. Bioorganic and Medicinal Chemistry. 1995 Jan 1;3(10):1313-1324. https://doi.org/10.1016/0968-0896(95)00118-Z
Kador, Peter F. ; Lee, Yong S. ; Rodriguez, Libaniel ; Sato, Sanai ; Bartoszko-Malik, Anita ; Abdel-Ghany, Yasser S. ; Miller, Duane. / Identification of an aldose reductase inhibitor site by affinity labeling. In: Bioorganic and Medicinal Chemistry. 1995 ; Vol. 3, No. 10. pp. 1313-1324.
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