title: Insights into ligand-elicited activation of human constitutive androstane receptor based on novel agonists and three-dimensional quantitative structure-activity relationship.
abstract: The human constitutive androstane receptor (CAR, NR1I3) is an important regulator of xenobiotic metabolism and other physiological processes. So far, only few CAR agonists are known and no explicit mechanism has been proposed for their action. Thus, we aimed to generate a 3D QSAR model that could explain the molecular determinants of CAR agonist action. To obtain a sufficient number of agonists that cover a wide range of activity, we applied a virtual screening approach using both structure- and ligand-based methods. We identified 27 novel human CAR agonists on which a 3D QSAR model was generated. The model, complemented by coregulator recruitment and mutagenesis results, suggests a potential activation mechanism for human CAR and may serve to predict potential activation of CAR for compounds emerging from drug development projects or for chemicals undergoing toxicological risk assessment.
authors.affiliation: Departments of Pharmaceutics and Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Jyrkkärinne
authors.forename: Björn
authors.initials: B
authors.lastname: Windshügel
authors.forename: Toni
authors.initials: T
authors.lastname: Rönkkö
authors.forename: Anu J
authors.initials: AJ
authors.lastname: Tervo
authors.forename: Jenni
authors.initials: J
authors.lastname: Küblbeck
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
mesh_terms: D000090702:Constitutive Androstane Receptor; D016208:Databases, Factual; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000090702:Constitutive Androstane Receptor; D008024:Ligands; C000716327:NR1I3 protein, human; D004364:Pharmaceutical Preparations; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors