Combination of virtual screening and high throughput gene profiling for identification of novel liver X receptor modulators
Combination of virtual screening and high throughput gene profiling for identification of novel liver X receptor modulators
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DOI：
10.1021/jm7011326
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发表时间：
2008-04-10
影响因子：
7.3
通讯作者：
Xu, Kui
中科院分区：
文献类型：
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作者：
Cheng, Jie-Fei;Zapf, James;Xu, Kui
我们使用 GLIDE 和经过修饰的 LXR β 配体结合域 (LBD) 对内部化合物收集进行虚拟对接研究，然后使用 ArrayPlate mRNA 测定进行基因分析。从虚拟筛选的1308个化合物中，发现总共69个化合物上调LXRα和某些LXR调节基因（命中率：5.3%）。化合物 4 显示可显着诱导 THP-1 分化巨噬细胞中 LXR 靶基因（例如 ABCA1、ABCG1、APOE、SCD-1 和 SREBP-1c）的表达。体外结合测定证实 4 直接结合 LXR α 和 LXR β 并招募共激活肽 SRC-1。它作为全 LXR 激动剂，刺激 THP-1 分化巨噬细胞中的胆固醇流出，并诱导 HepG2 细胞中的脂肪生成。这项研究表明，虚拟筛选和高通量基因分析相结合是快速鉴定新型 LXR 调节剂的有效方法。
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.