title: Combination of virtual screening and high throughput gene profiling for identification of novel liver X receptor modulators.
abstract: We conducted virtual docking studies using GLIDE with modified LXRbeta ligand-binding domain (LBD) on internal compound collection followed by the gene profiling with ArrayPlate mRNA assay. A total of 69 compounds were found to upregulate LXRalpha and certain LXR regulated genes from 1308 compounds selected by virtual screen (hit rate: 5.3%). Compound 4 was shown to significantly induce the expression of LXR target genes such as ABCA1, ABCG1, APOE, SCD-1, and SREBP-1c in THP-1 differentiated macrophages. In vitro binding assay confirmed that 4 binds to both LXRalpha and LXRbeta directly and recruits coactivator peptide SRC-1. It functions as a full LXR agonist in stimulating cholesterol efflux in THP-1 differentiated macrophages and induces lipogenesis in HepG2 cells. This study demonstrates that the combination of virtual screen and high throughput gene profiling is an efficient approach for rapid identification of novel LXR modulators.
authors.affiliation: Tanabe Research Laboratories USA, Inc., 4540 Towne Centre Court, San Diego, CA 92121, USA. jaycheng2008@gmail.com
authors.forename: Jie-Fei
authors.initials: JF
authors.lastname: Cheng
authors.forename: James
authors.initials: J
authors.lastname: Zapf
authors.forename: Kei
authors.initials: K
authors.lastname: Takedomi
authors.forename: Chiaki
authors.initials: C
authors.lastname: Fukushima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ogiku
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Zhang
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Naoki
authors.initials: N
authors.lastname: Sakurai
authors.forename: Miguel
authors.initials: M
authors.lastname: Barbosa
authors.forename: Rick
authors.initials: R
authors.lastname: Jack
authors.forename: Kui
authors.initials: K
authors.lastname: Xu
mesh_terms: D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D008958:Models, Molecular; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D057093:Orphan Nuclear Receptors; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D013261:Sterols / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001565:Benzoates; D001596:Benzylamines; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010620:Phenazocine; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013261:Sterols; D013449:Sulfonamides; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides