Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation
Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation
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通过虚拟筛选和生物学评价发现新型过氧化物酶体增殖物激活受体α (PPARα) 激动剂
DOI：
10.1021/acs.jcim.9b00838
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发表时间：
2020-03-23
影响因子：
5.6
通讯作者：
Yuan, Haoliang
中科院分区：
文献类型：
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作者：
Dai, Liang;Feng, Zhiqi;Yuan, Haoliang
非酒精性脂肪性肝炎（NASH）是世界范围内肝硬化和肝细胞癌的重要病因之一。PPAR α在肝脏中高度表达，在肝脏脂质代谢中起关键作用。我们对PPAR α激动剂治疗的人源化小鼠和NASH患者肝脏基因表达谱的分析表明，PPAR α可能是NASH治疗的潜在靶点。这促使我们寻找新的PPAR α激动剂。虚拟筛选和生物学评价结果表明，化合物a -4是一种选择性PPAR α激动剂。显著调节PPARa参与脂肪酸代谢和炎症的靶基因，表现出细胞抗炎活性。通过分子动力学（MD）模拟揭示了PPARa配体结合域（LBD）与化合物A-4结合的关键残基，并进一步通过突变研究进行了实验验证。综上所述，化合物a -4被认为是一种新型先导化合物，可用于开发强效和选择性的PPAR α激动剂。
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.