title: Identification of PPARgamma partial agonists of natural origin (I): development of a virtual screening procedure and in vitro validation.
abstract: BACKGROUND
  Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural products.
  
  
  RESULTS
  We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPARγ partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPARγ partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPARγ partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPARγ partial agonists: they bind to PPARγ, do not or only moderately stimulate the transactivation activity of PPARγ, do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes.
  
  
  CONCLUSIONS
  We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPARγ partial agonists.
authors.affiliation: Grup de Recerca en Nutrigenòmica, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Guasch
authors.forename: Esther
authors.initials: E
authors.lastname: Sala
authors.forename: Anna
authors.initials: A
authors.lastname: Castell-Auví
authors.forename: Lidia
authors.initials: L
authors.lastname: Cedó
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Markus
authors.initials: M
authors.lastname: Muehlbacher
authors.forename: Miquel
authors.initials: M
authors.lastname: Mulero
authors.forename: Montserrat
authors.initials: M
authors.lastname: Pinent
authors.forename: Anna
authors.initials: A
authors.lastname: Ardévol
authors.forename: Cristina
authors.initials: C
authors.lastname: Valls
authors.forename: Gerard
authors.initials: G
authors.lastname: Pujadas
authors.forename: Santiago
authors.initials: S
authors.lastname: Garcia-Vallvé
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001688:Biological Products / Q000378:metabolism / Q000494:pharmacology*; D062313:Databases, Pharmaceutical; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D054333:Drug Partial Agonism; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D015203:Reproducibility of Results; D014584:User-Computer Interface
chemical_list: D001688:Biological Products; D007004:Hypoglycemic Agents; D047495:PPAR gamma