The aldose reductase inhibitor site

Peter F. Kador, Jin H. Kinoshita, Norman E. Sharpless

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Evidence linking the enzyme aldose reductase (alditol:NADP+ oxidoreductase, EC 1.1.1.21) to the pathogenesis of several diabetic complications is rapidly mounting. The results of several animal studies combined with preliminary reports of ongoing clinical trials indicate that inhibition of aldose reductase produces a beneficial effect against such diabetic complications as neuropathy, cataract, corneal epitheliopathy, retinopathy, microangiopathy, and possibly nephropathy.1,2 The observations that aldose reductase inhibitors appear to provide a new direct mode of treatment for the control of diabetic complications-a method independent of the insulin-related control of blood glucose levels-has spurred interest in the development of more potent and selective inhibitors. That goal can be more easily realized through an understanding of how these inhibitors interact with the aldose reductase protein. This requires insight into the steric and electronic requirements of both the inhibitors and the enzyme site where they bind (inhibitor site). Through the use of computer molecular modeling, molecular orbital calculations, known structure-activity relationships (SAR), protein modification reagents, and irreversible inhibitors, specific structural, and electronic similarities among the apparently structurally diverse aldose reductase inhibitors (ARIs) have been observed.3,4 In turn, these studies have led us to postulate the pharmacophor requirements of the ARI site.

Original languageEnglish (US)
Pages (from-to)109-113
Number of pages5
JournalMetabolism
Volume35
Issue number4 SUPPL. 1
DOIs
StatePublished - Apr 1986

Fingerprint

Aldehyde Reductase
Diabetes Complications
Molecular Computers
Sugar Alcohols
Enzyme Inhibitors
Structure-Activity Relationship
NADP
Cataract
Blood Glucose
Oxidoreductases
Proteins
Clinical Trials
Insulin
Enzymes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Kador, P. F., Kinoshita, J. H., & Sharpless, N. E. (1986). The aldose reductase inhibitor site. Metabolism, 35(4 SUPPL. 1), 109-113. https://doi.org/10.1016/0026-0495(86)90198-8

The aldose reductase inhibitor site. / Kador, Peter F.; Kinoshita, Jin H.; Sharpless, Norman E.

In: Metabolism, Vol. 35, No. 4 SUPPL. 1, 04.1986, p. 109-113.

Research output: Contribution to journalArticle

Kador, PF, Kinoshita, JH & Sharpless, NE 1986, 'The aldose reductase inhibitor site', Metabolism, vol. 35, no. 4 SUPPL. 1, pp. 109-113. https://doi.org/10.1016/0026-0495(86)90198-8
Kador PF, Kinoshita JH, Sharpless NE. The aldose reductase inhibitor site. Metabolism. 1986 Apr;35(4 SUPPL. 1):109-113. https://doi.org/10.1016/0026-0495(86)90198-8
Kador, Peter F. ; Kinoshita, Jin H. ; Sharpless, Norman E. / The aldose reductase inhibitor site. In: Metabolism. 1986 ; Vol. 35, No. 4 SUPPL. 1. pp. 109-113.
@article{a10f72825a854ccbbf3cddec4b77fdd4,
title = "The aldose reductase inhibitor site",
abstract = "Evidence linking the enzyme aldose reductase (alditol:NADP+ oxidoreductase, EC 1.1.1.21) to the pathogenesis of several diabetic complications is rapidly mounting. The results of several animal studies combined with preliminary reports of ongoing clinical trials indicate that inhibition of aldose reductase produces a beneficial effect against such diabetic complications as neuropathy, cataract, corneal epitheliopathy, retinopathy, microangiopathy, and possibly nephropathy.1,2 The observations that aldose reductase inhibitors appear to provide a new direct mode of treatment for the control of diabetic complications-a method independent of the insulin-related control of blood glucose levels-has spurred interest in the development of more potent and selective inhibitors. That goal can be more easily realized through an understanding of how these inhibitors interact with the aldose reductase protein. This requires insight into the steric and electronic requirements of both the inhibitors and the enzyme site where they bind (inhibitor site). Through the use of computer molecular modeling, molecular orbital calculations, known structure-activity relationships (SAR), protein modification reagents, and irreversible inhibitors, specific structural, and electronic similarities among the apparently structurally diverse aldose reductase inhibitors (ARIs) have been observed.3,4 In turn, these studies have led us to postulate the pharmacophor requirements of the ARI site.",
author = "Kador, {Peter F.} and Kinoshita, {Jin H.} and Sharpless, {Norman E.}",
year = "1986",
month = "4",
doi = "10.1016/0026-0495(86)90198-8",
language = "English (US)",
volume = "35",
pages = "109--113",
journal = "Metabolism: Clinical and Experimental",
issn = "0026-0495",
publisher = "W.B. Saunders Ltd",
number = "4 SUPPL. 1",

}

TY - JOUR

T1 - The aldose reductase inhibitor site

AU - Kador, Peter F.

AU - Kinoshita, Jin H.

AU - Sharpless, Norman E.

PY - 1986/4

Y1 - 1986/4

N2 - Evidence linking the enzyme aldose reductase (alditol:NADP+ oxidoreductase, EC 1.1.1.21) to the pathogenesis of several diabetic complications is rapidly mounting. The results of several animal studies combined with preliminary reports of ongoing clinical trials indicate that inhibition of aldose reductase produces a beneficial effect against such diabetic complications as neuropathy, cataract, corneal epitheliopathy, retinopathy, microangiopathy, and possibly nephropathy.1,2 The observations that aldose reductase inhibitors appear to provide a new direct mode of treatment for the control of diabetic complications-a method independent of the insulin-related control of blood glucose levels-has spurred interest in the development of more potent and selective inhibitors. That goal can be more easily realized through an understanding of how these inhibitors interact with the aldose reductase protein. This requires insight into the steric and electronic requirements of both the inhibitors and the enzyme site where they bind (inhibitor site). Through the use of computer molecular modeling, molecular orbital calculations, known structure-activity relationships (SAR), protein modification reagents, and irreversible inhibitors, specific structural, and electronic similarities among the apparently structurally diverse aldose reductase inhibitors (ARIs) have been observed.3,4 In turn, these studies have led us to postulate the pharmacophor requirements of the ARI site.

AB - Evidence linking the enzyme aldose reductase (alditol:NADP+ oxidoreductase, EC 1.1.1.21) to the pathogenesis of several diabetic complications is rapidly mounting. The results of several animal studies combined with preliminary reports of ongoing clinical trials indicate that inhibition of aldose reductase produces a beneficial effect against such diabetic complications as neuropathy, cataract, corneal epitheliopathy, retinopathy, microangiopathy, and possibly nephropathy.1,2 The observations that aldose reductase inhibitors appear to provide a new direct mode of treatment for the control of diabetic complications-a method independent of the insulin-related control of blood glucose levels-has spurred interest in the development of more potent and selective inhibitors. That goal can be more easily realized through an understanding of how these inhibitors interact with the aldose reductase protein. This requires insight into the steric and electronic requirements of both the inhibitors and the enzyme site where they bind (inhibitor site). Through the use of computer molecular modeling, molecular orbital calculations, known structure-activity relationships (SAR), protein modification reagents, and irreversible inhibitors, specific structural, and electronic similarities among the apparently structurally diverse aldose reductase inhibitors (ARIs) have been observed.3,4 In turn, these studies have led us to postulate the pharmacophor requirements of the ARI site.

UR - http://www.scopus.com/inward/record.url?scp=0022624260&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0022624260&partnerID=8YFLogxK

U2 - 10.1016/0026-0495(86)90198-8

DO - 10.1016/0026-0495(86)90198-8

M3 - Article

C2 - 3083201

AN - SCOPUS:0022624260

VL - 35

SP - 109

EP - 113

JO - Metabolism: Clinical and Experimental

JF - Metabolism: Clinical and Experimental

SN - 0026-0495

IS - 4 SUPPL. 1

ER -