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 D. Miller

Research output: Contribution to journalArticle

15 Scopus citations

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 - Oct 1995

ASJC Scopus subject areas

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

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  • Cite this

    Kador, P. F., Lee, Y. S., Rodriguez, L., Sato, S., Bartoszko-Malik, A., Abdel-Ghany, Y. S., & Miller, D. 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