Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity
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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.
KeywordsPPARgamma Antidiabetics PPARgamma partial agonists Drug design 3D-QSAR
Ligand binding domain
Peroxisome proliferator-activated receptor
Quantitative structure–activity relationship
Structure activity relationship
This manuscript was edited for English language fluency by American Journal Experts. This study was supported by Grant Number AGL2008-00387/ALI from the Ministerio de Educación y Ciencia of the Spanish Government and the ACC1Ó (TECCT10-1-0008) program (Generalitat de Catalunya). The authors wish to thank the Servei de Disseny de Fàrmacs (Drug Design Service) of the Catalonia Supercomputer Center (CESCA) for providing access to Schrödinger software.
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