Journal
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 25, Issue 8, Pages 717-728Publisher
SPRINGER
DOI: 10.1007/s10822-011-9446-9
Keywords
PPARgamma; Antidiabetics; PPARgamma partial agonists; Drug design; 3D-QSAR
Categories
Funding
- Ministerio de Educacion y Ciencia of the Spanish Government [AGL2008-00387/ALI]
- Generalitat de Catalunya [ACC1O (TECCT10-1-0008)]
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Peroxisome Proliferator-Activated Receptor c (PPARc) 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 PPARc 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 PPARc agonists to explore the different binding features of full and partial PPARc agonists with the aim of differentiating the features needed for binding and those needed for the transactivation activity of PPARc. 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 PPARc partial agonists.
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