2ath
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Crystal structure of the ligand binding domain of human PPAR-gamma im complex with an agonist
OverviewOverview
The synthesis and structure-activity relationship studies of novel indole, derivatives as peroxisome proliferator-activated receptor (PPAR) agonists, are reported. Indole, a drug-like scaffold, was studied as a core skeleton, for the acidic head part of PPAR agonists. The structural features (acidic, head, substitution on indole, and linker) were optimized first, by keeping, benzisoxazole as the tail part, based on binding and functional activity, at PPARgamma protein. The variations in the tail part, by introducing, various heteroaromatic ring systems, were then studied. In vitro, evaluation led to identification of a novel series of indole compounds, with a benzisoxazole tail as potent PPAR agonists with the lead compound, 14 (BPR1H036) displaying an excellent pharmacokinetic profile in BALB/c, mice and an efficacious glucose lowering activity in KKA(y) mice., Structural biology studies of 14 showed that the indole ring contributes, strong hydrophobic interactions with PPARgamma and could be an important, moiety for the binding to the protein.
DiseaseDisease
Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[601487], Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension OMIM:[601487], Glioblastoma, susceptibility to OMIM:[601487], Insulin resistance, severe, digenic OMIM:[601487], Lipodystrophy, familial partial OMIM:[601487], Obesity, resistance to OMIM:[601487], Obesity, severe OMIM:[601487]
About this StructureAbout this Structure
2ATH is a Single protein structure of sequence from Homo sapiens with 3EA as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities., Mahindroo N, Huang CF, Peng YH, Wang CC, Liao CC, Lien TW, Chittimalla SK, Huang WJ, Chai CH, Prakash E, Chen CP, Hsu TA, Peng CH, Lu IL, Lee LH, Chang YW, Chen WC, Chou YC, Chen CT, Goparaju CM, Chen YS, Lan SJ, Yu MC, Chen X, Chao YS, Wu SY, Hsieh HP, J Med Chem. 2005 Dec 29;48(26):8194-208. PMID:16366601
Page seeded by OCA on Mon Nov 12 20:54:35 2007