Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation

被引：11

作者：

Dai, Liang ^{[1
,2
]}

Feng, Zhiqi ^{[1
,2
]}

Zha, Rili ^{[1
,2
]}

Cheng, Keguang ^{[3
]}

Wen, Xiaoan ^{[1
,2
]}

Sun, Hongbin ^{[1
,2
]}

Yuan, Haoliang ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China

[3] Guangxi Normal Univ, Sch Chem & Pharm, State Key Lab Chem & Mol Engn Med Resources, Guilin 541004, Peoples R China

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2020年 / 60卷 / 03期

基金：

中国国家自然科学基金;

关键词：

ALPHA/GAMMA DUAL AGONISTS; FARNESOID X RECEPTOR; FATTY LIVER-DISEASE; GENE-EXPRESSION; ACID-DERIVATIVES; STRUCTURAL BASIS; BETA-OXIDATION; HIGHLY POTENT; FIBROSIS; INHIBITORS;

D O I：

10.1021/acs.jcim.9b00838

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Nonalcoholic steatohepatitis (NASH) is one of the important causes of cirrhosis and hepatocellular carcinoma worldwide. PPAR alpha is highly expressed in the liver and plays a critical role in hepatic lipid metabolism. Our analysis of the gene expression profiles in the liver of humanized mice treated with a PPAR alpha agonist and NASH patients suggested that PPAR alpha might be a potential target for NASH therapy. This promoted us to find novel PPAR alpha agonists. The results of virtual screening and biological evaluation identified compound A-4 as a selective PPAR alpha agonist. It significantly regulated the target genes of PPARa involved in fatty acid metabolism and inflammation, exhibiting cellular anti-inflammatory activity. The key residues involved in the binding between PPARa ligand-binding domain (LBD) and compound A-4 were revealed by molecular dynamics (MD) simulation and further experimentally validated by the mutation study. Together, compound A-4 was well characterized as a novel lead compound for developing potent and selective PPAR alpha agonists.

引用

页码：1717 / 1727

页数：11

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