Molecular Modeling Study of Species-Selective Peroxisome Proliferator-Activated Receptor (PPAR) α Agonist ; Possible Mechanism(s) of Human PPARα Selectivity of an α-Substituted Phenylpropanoic Acid Derivative (KCL)
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概要
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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 PPARaα. 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.
- 公益社団法人日本薬学会の論文
- 2004-03-01
著者
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Miyachi Hiroyuki
Institute Of Molecular & Cellular Biosciences University Of Tokyo
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Miyachi Hiroyuki
Discovery Research Laboratories Kyorin Pharmaceutical Co. Ltd.
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Miyachi H
Institute Of Molecular & Cellular Biosciences The University Of Tokyo
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Miyachi Hiroyuki
Div. Of Pharmaceutical Sciences Graduate School Of Medicine Dentistry And Pharmaceutical Sciences Ok
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UCHIKI Hideharu
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd.
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Uchiki Hideharu
Discovery Research Laboratories Kyorin Pharmaceutical Co. Ltd.
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