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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
Author(s) -
Kasuga Junichi,
Oyama Takuji,
Nakagome Izumi,
Makishima Makoto,
Hirono Shuichi,
Morikawa Kosuke,
Hashimoto Yuichi,
Miyachi Hiroyuki
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800193
Subject(s) - agonist , selectivity , chemistry , docking (animal) , peroxisome proliferator activated receptor , amino acid , receptor , stereochemistry , peroxisome , biochemistry , medicine , nursing , catalysis
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.