Discovery of novel liver X receptor inverse agonists as lipogenesis inhibitors

被引:16
作者
Chen, Ziyang [1 ,2 ]
Chen, Hao [1 ]
Zhang, Zizhen [1 ]
Ding, Peng [1 ]
Yan, Xin [1 ]
Li, Yanwen [3 ]
Zhang, Songxuan [1 ]
Gu, Qiong [1 ]
Zhou, Huihao [1 ]
Xu, Jun [1 ,3 ]
机构
[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Res Ctr Drug Discovery, Guangzhou 510006, Peoples R China
[2] Shenzhen Pingshan Tradit Chinese Med Hosp, Shenzhen Pingle Orthopaed Hosp, Shenzhen 518118, Peoples R China
[3] Wuyi Univ, Sch Biotechnol & Hlth Sci, Jiangmen 529020, Peoples R China
基金
中国国家自然科学基金;
关键词
Liver X receptor; Inverse agonists; Lipogenesis; Hyperlipidemia; LXR-BETA; PATHWAYS; CHALLENGES; AMBER;
D O I
10.1016/j.ejmech.2020.112793
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Based on the co-crystal structures of LXR beta and its agonists (spiro [pyrrolidine-3,3'-oxindole] derivatives) discovered by us previously, we designed and synthesized a compound library to explore the agonistic activities. The library was screened with luciferase reporter assays, interestingly, it resulted in the discovery of 10 LXR inverse agonists besides 5 LXR agonists. To clarify the mechanism of the actions, we conducted molecular dynamics (MD) simulations on the LXR and inverse agonists complexes, and revealed that H3, H11 and H12 configurations are the key to turn on agonism or inverse agonism status for LXR. Binding tightly with H3, pushing H11 out and destabilizing H12 could form a bigger hydrophobic groove to accommodate NCOR1 to turn on LXR inverse agonism. The inverse agonist lOrr was further studied, and found as a lipogenesis inhibitor through down-regulating LXR target genes SREBP-1c, ACC, FAS and SCD-1, and demonstrated lipid-lowering effects in 3T3-L1 cells, HepG2 cells and mice with Triton WR-1339-induced hyperlipidemia. Therefore, we have proved that LXR inverse agonists can be promising agents for hyperlipidemia treatment. (C) 2020 Elsevier Masson SAS. All rights reserved.
引用
收藏
页数:16
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