title: Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening.
abstract: Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested positive in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compounds 5, 7, and 8 were identified as PPAR-alpha agonists, whereas compounds 2 and 9 showed agonistic activity for hPPAR-gamma. Moreover, compound 9 was identified as a PPAR-delta antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidaemia, and type 2 diabetes.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Rasmus K
authors.initials: RK
authors.lastname: Petersen
authors.forename: Esben N
authors.initials: EN
authors.lastname: Flindt
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.forename: Gudrun
authors.initials: G
authors.lastname: Spitzer
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Christian
authors.initials: C
authors.lastname: Laggner
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
mesh_terms: D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical; D006801:Humans; D021621:Imaging, Three-Dimensional; D008024:Ligands; D008958:Models, Molecular; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors