Determination of the critical amino acids involved in the peroxisome proliferator-activated receptor (PPAR) δ selectivity of phenylpropanoic acid-derived agonists

Jun Ichi Kasuga; Takuji Oyama; Izumi Nakagome; Makoto Makishima; Shuichi Hirono; Kosuke Morikawa; Yuichi Hashimoto; Hiroyuki Miyachi

doi:10.1002/cmdc.200800193

Determination of the critical amino acids involved in the peroxisome proliferator-activated receptor (PPAR) δ selectivity of phenylpropanoic acid-derived agonists

Jun Ichi Kasuga, Takuji Oyama, Izumi Nakagome, Makoto Makishima, Shuichi Hirono, Kosuke Morikawa, Yuichi Hashimoto, Hiroyuki Miyachi

School of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

Phenylpropanoic acid-derived PPAR agonist TIPP-204, shows high selectivity for human (h)PPARδ while structurally related TIPP-401 is a hPPARα/δ dual agonist. Computational docking of TIPP-401 in the ligand binding domain (LBD) of hPPARα and hPPARδ, and inspection of the TIPP-204-hPPARδ LBD co-crystal structure identified key amino acids responsible for the differences in selectivity of the two analogues. These results were confirmed using mutagenesis assays. The amino acids determining the potency and selectivity of TIPP-204 are different to those of the PPARδ-selective agonist GW-501516, which belongs to a different chemical class. (Chemical Equation Presented).

Original language	English
Pages (from-to)	1662-1666
Number of pages	5
Journal	ChemMedChem
Volume	3
Issue number	11
DOIs	https://doi.org/10.1002/cmdc.200800193
Publication status	Published - Nov 17 2008

Keywords

Mutagenesis
PPARδ-selective agonists
Protein structures
Receptors
X-ray crystallography

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
Pharmacology, Toxicology and Pharmaceutics(all)
Organic Chemistry

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10.1002/cmdc.200800193

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title = "Determination of the critical amino acids involved in the peroxisome proliferator-activated receptor (PPAR) δ selectivity of phenylpropanoic acid-derived agonists",

abstract = "Phenylpropanoic acid-derived PPAR agonist TIPP-204, shows high selectivity for human (h)PPARδ while structurally related TIPP-401 is a hPPARα/δ dual agonist. Computational docking of TIPP-401 in the ligand binding domain (LBD) of hPPARα and hPPARδ, and inspection of the TIPP-204-hPPARδ LBD co-crystal structure identified key amino acids responsible for the differences in selectivity of the two analogues. These results were confirmed using mutagenesis assays. The amino acids determining the potency and selectivity of TIPP-204 are different to those of the PPARδ-selective agonist GW-501516, which belongs to a different chemical class. (Chemical Equation Presented).",

keywords = "Mutagenesis, PPARδ-selective agonists, Protein structures, Receptors, X-ray crystallography",

author = "Kasuga, {Jun Ichi} and Takuji Oyama and Izumi Nakagome and Makoto Makishima and Shuichi Hirono and Kosuke Morikawa and Yuichi Hashimoto and Hiroyuki Miyachi",

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doi = "10.1002/cmdc.200800193",

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AU - Kasuga, Jun Ichi

AU - Oyama, Takuji

AU - Nakagome, Izumi

AU - Makishima, Makoto

AU - Hirono, Shuichi

AU - Morikawa, Kosuke

AU - Hashimoto, Yuichi

AU - Miyachi, Hiroyuki

PY - 2008/11/17

Y1 - 2008/11/17

N2 - Phenylpropanoic acid-derived PPAR agonist TIPP-204, shows high selectivity for human (h)PPARδ while structurally related TIPP-401 is a hPPARα/δ dual agonist. Computational docking of TIPP-401 in the ligand binding domain (LBD) of hPPARα and hPPARδ, and inspection of the TIPP-204-hPPARδ LBD co-crystal structure identified key amino acids responsible for the differences in selectivity of the two analogues. These results were confirmed using mutagenesis assays. The amino acids determining the potency and selectivity of TIPP-204 are different to those of the PPARδ-selective agonist GW-501516, which belongs to a different chemical class. (Chemical Equation Presented).

AB - Phenylpropanoic acid-derived PPAR agonist TIPP-204, shows high selectivity for human (h)PPARδ while structurally related TIPP-401 is a hPPARα/δ dual agonist. Computational docking of TIPP-401 in the ligand binding domain (LBD) of hPPARα and hPPARδ, and inspection of the TIPP-204-hPPARδ LBD co-crystal structure identified key amino acids responsible for the differences in selectivity of the two analogues. These results were confirmed using mutagenesis assays. The amino acids determining the potency and selectivity of TIPP-204 are different to those of the PPARδ-selective agonist GW-501516, which belongs to a different chemical class. (Chemical Equation Presented).

KW - Mutagenesis

KW - PPARδ-selective agonists

KW - Protein structures

KW - Receptors

KW - X-ray crystallography

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Determination of the critical amino acids involved in the peroxisome proliferator-activated receptor (PPAR) δ selectivity of phenylpropanoic acid-derived agonists

Abstract

Keywords

ASJC Scopus subject areas

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