Linked Life Data

18086153

Source:http://linkedlifedata.com/resource/pubmed/id/18086153

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2008-1-11
pubmed:abstractText
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays an essential role in lipid and glucose homeostasis. It is recognized as the receptor of the thiazolidinediones-a synthetic class of anti-diabetic drugs-and is the target of many drug discovery efforts because of its role in disease states, such as type II diabetes mellitus. In this study, structure-based virtual screening of the PPAR-gamma ligand binding domain against a natural product library has revealed 29 potential agonists. In vitro testing of this list identified six flavonoids to have stimulated PPAR-gamma transcriptional activity in a transcriptional factor assay. Of these, flavonoid-psi-baptigenin-was classed as the most potent PPAR-gamma agonist, possessing low micromolar affinity (EC(50) = 2.9 microM). Further in vitro testing using quantitative RT-PCR and immunoblotting experiments demonstrated that psi-baptigenin activated PPAR-gamma mRNA (4.1 +/- 0.2-fold) and protein levels (2.9 +/- 0.4-fold) in THP-1 macrophages. Moreover, psi-baptigenin's-induced PPAR-gamma enhancement was abolished in the presence of a selective PPAR-gamma antagonist, GW9662. Induced-fit docking investigations provide a detailed understanding on the ligands' mechanism of action, suggesting five of the active flavonoids induce significant conformational change in the receptor upon binding. Overall, these results offer insight into various naturally derived flavonoids as leads/templates for development of novel PPAR-gamma ligands.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1747-0285
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
71
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
57-70
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Novel PPAR-gamma agonists identified from a natural product library: a virtual screening, induced-fit docking and biological assay study.
pubmed:affiliation
Faculty of Pharmacy, University of Sydney, NSW 2006, Australia.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't