Combination of virtual screening and high throughput gene profiling for identification of novel liver X receptor modulators

被引：9

作者：

Cheng, Jie-Fei ^{[1
]}

Zapf, James ^{[1
]}

Takedomi, Kei ^{[2
]}

Fukushima, Chiaki ^{[2
]}

Ogiku, Tsuyoshi ^{[2
]}

Zhang, Shao-Hui ^{[1
]}

Yang, Guang ^{[1
]}

Sakurai, Naoki ^{[1
]}

Barbosa, Miguel ^{[1
]}

Jack, Rick ^{[1
]}

Xu, Kui ^{[1
]}

机构：

[1] Tanabe Res Labs USA Inc, San Diego, CA 92121 USA

[2] Tanabe Seiyaku Co Ltd, Med Chem Res Labs, Saitama 3358505, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 07期

关键词：

D O I：

10.1021/jm7011326

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We conducted virtual docking studies using GLIDE with modified LXR beta 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 LXR alpha 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 suchas ABCA1, ABCG1, APOE, SCD-1, and SREBP-1c in THP-1 differentiated macrophages. In vitro binding assay confirmed that 4 binds to both LXR alpha and LXR beta 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.

引用

页码：2057 / 2061

页数：5

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