title: Identification of novel liver X receptor activators by structure-based modeling.
abstract: Liver X receptors (LXRs) are members of the nuclear receptor family. Activators of LXRs are of high pharmacological interest as LXRs regulate cholesterol, fatty acid, and carbohydrate metabolism as well as inflammatory processes. On the basis of different X-ray crystal structures, we established a virtual screening workflow for the identification of novel LXR modulators. A two-step screening concept to identify active compounds included 3D-pharmacophore filters and rescoring by shape alignment. Eighteen virtual hits were tested in vitro applying a reporter gene assay, where concentration-dependent activity was proven for four novel lead structures. The most active compound 10, a 1,4-naphthochinone, has an estimated EC₅₀ of around 5 μM.
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry/Theoretical Chemistry and Center for Molecular Biosciences Innsbruck-CMBI, University of Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: von Grafenstein
authors.forename: Judit
authors.initials: J
authors.lastname: Mihaly-Bison
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Valery N
authors.initials: VN
authors.lastname: Bochkov
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
mesh_terms: D003198:Computer Simulation; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D008024:Ligands; D000071518:Liver X Receptors; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000737:chemistry* / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D054852:Small Molecule Libraries