Combination of virtual screening and high throughput gene profiling for identification of novel liver X receptor modulators.
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.
Cheng
Jie-Fei
JF
Tanabe Research Laboratories USA, Inc., 4540 Towne Centre Court, San Diego, CA 92121, USA. jaycheng2008@gmail.com
Zapf
James
J
Takedomi
Kei
K
Fukushima
Chiaki
C
Ogiku
Tsuyoshi
T
Zhang
Shao-Hui
SH
Yang
Guang
G
Sakurai
Naoki
N
Barbosa
Miguel
M
Jack
Rick
R
Xu
Kui
K
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
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