Paper Info
Title
Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity.
Abstract
Peroxisome Proliferator-Activated Receptor γ (PPARγ) full agonists are molecules with powerful insulin-sensitizing action that are used as antidiabetic drugs. Unfortunately, these compounds also present various side effects. Recent results suggest that effective PPARγ agonists should show a low transactivation activity but a high binding affinity to inhibit phosphorylation at Ser273. We use several structure activity relationship studies of synthetic PPARγ agonists to explore the different binding features of full and partial PPARγ agonists with the aim of differentiating the features needed for binding and those needed for the transactivation activity of PPARγ. Our results suggest that effective partial agonists should have a hydrophobic moiety and an acceptor site with an appropriate conformation to interact with arm II and establish a hydrogen bond with Ser342 or an equivalent residue at arm III. Despite the fact that interactions with arm I increase the binding affinity, this region should be avoided in order to not increase the transactivation activity of potential PPARγ partial agonists.
Year
DOI
Venue
2011
10.1007/s10822-011-9446-9
Journal of computer-aided molecular design
Keywords
Field
DocType
PPARgamma,Antidiabetics,PPARgamma partial agonists,Drug design,3D-QSAR
Phosphorylation,Moiety,Ligand (biochemistry),Biophysics,Biochemistry,Computational chemistry,Partial agonist,Chemistry,Receptor,Structure–activity relationship,Peroxisome,Transactivation
Journal
Volume
Issue
ISSN
25
8
1573-4951
Citations 
PageRank 
References 
0
0.34
3
Authors
8
Name
Order
Citations
PageRank
Laura Guasch1122.14
Esther Sala200.34
Cristina Valls3141.51
Mayte Blay400.34
Miquel Mulero5141.51
Lluís Arola640.76
Gerard Pujadas7333.44
Santiago Garcia-Vallvé810510.71