Identification of 3H-benzo[b] [1,4] diazepine derivatives as PPARα agonists by in silico studies and biochemical evaluation

doi:10.1080/07391102.2023.2256867

KIB OpenIR

	Identification of 3H-benzo[b] [1,4] diazepine derivatives as PPARα agonists by in silico studies and biochemical evaluation
	Li,Yue; Lv,Mengjia; Shen,Meiling; Gu,Xi; Zhang,Li; Liu,Xingyong; Chen,Jing; Gong,Likun; Zuo,Zhili
	2023
发表期刊	JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
ISSN	1538-0254
页码	2256867
摘要	Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, whose pathologic features include dysregulated glucose homeostasis and lipid accumulation. Peroxisome proliferators-activated receptor a (PPAR alpha) is a key regulator of fatty acid metabolism and ketogenesis due to its regulatory pathways involve activating fatty acid uptake, accelerating fatty acid oxidation, inhibiting gluconeogenesis, and suppressing inflammation and fibrosis. Therefore, PPAR alpha is considered as a potential target for the treatment of NAFLD and some agonists have entered clinical trials, which drove us to discover more novel PPAR alpha agonists. In current work, new 3H-benzo[b] [1,4] diazepine PPAR alpha agonists were identified from the ChemDiv database by pharmacophore modeling, molecular docking, derivative structure search, and bioassays, where compound LY-2 and its derivatives (LY-10 similar to LY-19) were discovered to promote the expression of PPAR alpha downstream gene, carnitine palmitoyl transterase-1 alpha (cpt1 alpha). Among these active compounds, the EC50 value of LY-2 against increasing cpt1 alpha was 2.169 mu M. Furthermore, the effect of LY-2 on cpt1a was weakened when PPAR alpha knock down, which confirmed that it is a PPAR alpha agonist again. Finally, the results from molecular dynamics simulations and binding free energy calculations showed that pi-pi stacking and hydrogen bonding interactions played key roles in the binding of LY-2 and PPAR alpha protein and their complex maintained a stable structure to facilitate LY-2 to have a better binding affinity with PPAR alpha protein. Taken together, compound LY-2 might be a novel lead compound for the development of potent PPAR alpha agonists. [GRAPHICS] .
关键词	NAFLD PPAR alpha agonist virtual screening biochemical evaluation FATTY-ACID OXIDATION GROMACS
DOI	10.1080/07391102.2023.2256867
收录类别	SCI
WOS记录号	WOS:001065166300001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75608
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Li,Yue,Lv,Mengjia,Shen,Meiling,et al. Identification of 3H-benzo[b] [1,4] diazepine derivatives as PPARα agonists by in silico studies and biochemical evaluation[J]. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS,2023:2256867.
APA	Li,Yue.,Lv,Mengjia.,Shen,Meiling.,Gu,Xi.,Zhang,Li.,...&Zuo,Zhili.(2023).Identification of 3H-benzo[b] [1,4] diazepine derivatives as PPARα agonists by in silico studies and biochemical evaluation.JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS,2256867.
MLA	Li,Yue,et al."Identification of 3H-benzo[b] [1,4] diazepine derivatives as PPARα agonists by in silico studies and biochemical evaluation".JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS (2023):2256867.

条目包含的文件		下载所有文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
1722405775_38097_8e9（3338KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	浏览下载