Molecular modeling study of species-selective peroxisome proliferator-activated receptor (PPAR) αagonist; possible mechanism(s) of human PPARα selectivity of an α-substituted phenylpropanoic acid derivative (KCL)

Hideharu Uchiki, Hiroyuki Miyachi

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

In order to investigate the reason why phenylpropanoic acid derivative (KCL), a potent, human peroxisome proliferator-activated receptor (PPAR) α-selective agonist, shows this selectivity, we analyzed the binding modes of KCL and a related compound to the ligand-binding domain of human PPARα and rat PPARα by means of computer-aided molecular modeling. We concluded that the characteristic specificity of KCL is due to a specific hydrophobic contact between the hydrophobic tail part (the 4-trifluoromethyl group) and the key amino acid Ile272 located on the helix three region of the human PPARα ligand binding domain. We propose a possible binding mode of KCL with the ligand-binding domain of human PPARα. This binding model should offer important insights for further structural design of subtype-selective PPARα agonists for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.

Original languageEnglish
Pages (from-to)365-367
Number of pages3
JournalChemical and Pharmaceutical Bulletin
Volume52
Issue number3
DOIs
Publication statusPublished - Mar 2004
Externally publishedYes

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Peroxisome Proliferator-Activated Receptors
Molecular modeling
Derivatives
Acids
Ligands
Molecular Computers
Medical problems
Dyslipidemias
Structural design
Tail
Rats
Homeostasis
Obesity
Amino Acids

Keywords

  • KCL
  • Molecular modeling
  • Mutation
  • Peroxisome proliferator-activated receptor (PPAR) α
  • Species-selectivity

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Pharmacology

Cite this

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N2 - In order to investigate the reason why phenylpropanoic acid derivative (KCL), a potent, human peroxisome proliferator-activated receptor (PPAR) α-selective agonist, shows this selectivity, we analyzed the binding modes of KCL and a related compound to the ligand-binding domain of human PPARα and rat PPARα by means of computer-aided molecular modeling. We concluded that the characteristic specificity of KCL is due to a specific hydrophobic contact between the hydrophobic tail part (the 4-trifluoromethyl group) and the key amino acid Ile272 located on the helix three region of the human PPARα ligand binding domain. We propose a possible binding mode of KCL with the ligand-binding domain of human PPARα. This binding model should offer important insights for further structural design of subtype-selective PPARα agonists for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.

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