title: Identification of a novel selective PPARγ ligand with a unique binding mode and improved therapeutic profile in vitro.
abstract: Thiazolidinediones (TZD) function as potent anti-diabetic drugs through their direct action on the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), but their therapeutic benefits are compromised by severe side effects. To address this concern, here we developed a potent "hit" compound, VSP-51, which is a novel selective PPARγ-modulating ligand with improved therapeutic profiles in vitro compared to the multi-billion dollar TZD drug rosiglitazone (Rosi). Unlike Rosi, VSP-51 is a partial agonist of PPARγ with improved insulin sensitivity due to its ability to bind PPARγ with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. We have determined the crystal structure of the PPARγ ligand-binding domain (LBD) in complex with VSP-51, which revealed a unique mode of binding for VSP-51 and provides the molecular basis for the discrimination between VSP-51 from TZDs and other ligands such as telmisartan, SR1663 and SR1664. Taken together, our findings demonstrate that: a) VSP-51 can serve as a promising candidate for anti-diabetic drug discovery; and b) provide a rational basis for the development of future pharmacological agents targeting PPARγ with advantages over current TZD drugs.
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou 511436, P. R. China.|VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Shi
authors.affiliation: VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
authors.forename: Guanguan
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Laboratory of Structural Sciences, Program of Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: X Edward
authors.initials: XE
authors.lastname: Zhou
authors.affiliation: Laboratory of Structural Sciences, Program of Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Suino-Powell
authors.affiliation: Laboratory of Structural Sciences, Program of Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.affiliation: VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.|Laboratory of Structural Sciences, Program of Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D018360:Crystallography, X-Ray; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*
chemical_list: D007211:Indoles; D008024:Ligands; D047495:PPAR gamma; D008156:Luciferases