Cheng Jie-Fei, Zapf James, Takedomi Kei, Fukushima Chiaki, Ogiku Tsuyoshi, Zhang Shao-Hui, Yang Guang, Sakurai Naoki, Barbosa Miguel, Jack Rick, Xu Kui
Tanabe Research Laboratories USA, Inc., 4540 Towne Centre Court, San Diego, CA 92121, USA.
J Med Chem. 2008 Apr 10;51(7):2057-61. doi: 10.1021/jm7011326. Epub 2008 Mar 7.
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.
