Molecular modeling studies of the binding modes of aldose reductase inhibitors at the active site of human aldose reductase

Yong S. Lee, Zhou Chen, Peter F. Kador

Research output: Contribution to journalArticle

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Abstract

Molecular modeling studies using the CHARMM method have been conducted to study the binding modes of aldose reductase inhibitors at the active site of aldose reductase. The energy minimized structures of aldose reductase with six structurally diverse inhibitors (spirofluorene-9,5'-imidazolidine-2',4'-dione (1), 9-fluoreneacetic acid (2), AL1576 (3), 2,7-difluoro-9-fluoreneacetic acid (4), FK366 (5), and Epalrestat (9)) indicate that the side chains of Tyr48, His110, and Trp111 can form numerous hydrogen bonds with either the carboxylate or the hydantoin group of the inhibitors while the side chains of Trp20, Trp111, and Phe122 are positioned to form aromatic-aromatic interactions. Of the three residues (Tyr 48, His 110, and Trp 111) that can form hydrogen bonds with the ionized portion of aldose reductase inhibitors, protonated His110 appears to play an important role in directing charged inhibitors to bind at the active site through charge interaction. Based on the binding mode of the inhibitors and their observed inhibitory activities, pharmacophore requirements for aldose reductase inhibitors are discussed. Copyright (C) 1998 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)1811-1819
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume6
Issue number10
DOIs
StatePublished - Oct 1 1998

Fingerprint

Aldehyde Reductase
Molecular modeling
Catalytic Domain
Hydrogen
Hydrogen bonds
Hydantoins

Keywords

  • Aldose reductase inhibitors
  • Aromatic-aromatic interaction
  • Charge interaction
  • Hydrogen bond
  • Pharmacophore requirements

ASJC Scopus subject areas

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

Cite this

Molecular modeling studies of the binding modes of aldose reductase inhibitors at the active site of human aldose reductase. / Lee, Yong S.; Chen, Zhou; Kador, Peter F.

In: Bioorganic and Medicinal Chemistry, Vol. 6, No. 10, 01.10.1998, p. 1811-1819.

Research output: Contribution to journalArticle

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