Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect

被引：21

作者：

Chen, Yankun ^{[1
]}

Chen, Xi ^{[1
]}

Luo, Ganggang ^{[1
]}

Zhang, Xu ^{[1
]}

Lu, Fang ^{[1
]}

Qiao, Liansheng ^{[1
]}

He, Wenjing ^{[2
]}

Li, Gongyu ^{[1
]}

Zhang, Yanling ^{[1
]}

机构：

[1] Beijing Univ Chinese Med, Sch Chinese Mat Med, Beijing 100102, Peoples R China

[2] Xinjiang Med Univ, Coll Tradit Chinese Med, Urumqi 830054, Peoples R China

来源：

MOLECULES | 2018年 / 23卷 / 05期

基金：

中国国家自然科学基金;

关键词：

hyperlipidemia; squalene synthase (SQS); molecular modeling; drug discovery; Traditional Chinese Medicine; MOLECULAR DOCKING; IDENTIFICATION; CHOLESTEROL; PHARMACOPHORE; DYNAMICS; KINASE; TOOL; TRIGLYCERIDE; DERIVATIVES; EXPRESSION;

D O I：

10.3390/molecules23051040

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Squalene synthase (SQS), a key downstream enzyme involved in the cholesterol biosynthetic pathway, plays an important role in treating hyperlipidemia. Compared to statins, SQS inhibitors have shown a very significant lipid-lowering effect and do not cause myotoxicity. Thus, the paper aims to discover potential SQS inhibitors from Traditional Chinese Medicine (TCM) by the combination of molecular modeling methods and biological assays. In this study, cynarin was selected as a potential SQS inhibitor candidate compound based on its pharmacophoric properties, molecular docking studies and molecular dynamics (MD) simulations. Cynarin could form hydrophobic interactions with PHE54, LEU211, LEU183 and PRO292, which are regarded as important interactions for the SQS inhibitors. In addition, the lipid-lowering effect of cynarin was tested in sodium oleate-induced HepG2 cells by decreasing the lipidemic parameter triglyceride (TG) level by 22.50%. Finally. cynarin was reversely screened against other anti-hyperlipidemia targets which existed in HepG2 cells and cynarin was unable to map with the pharmacophore of these targets, which indicated that the lipid-lowering effects of cynarin might be due to the inhibition of SQS. This study discovered cynarin is a potential SQS inhibitor from TCM, which could be further clinically explored for the treatment of hyperlipidemia.

引用

页数：18

共 33 条

[31] Screening of Sonic Hedgehog (Shh) Inhibitors in the Hedgehog Signaling Pathway from Traditional Chinese Medicine (TCM) Database Through Structure-Based Pharmacophore Design
Rizki, Ilmi Fadhilah
Nasution, Mochammad Arfin Fardiansyah
Siregar, Syafrida
Ekawati, Mega Maulina
Tambunan, Usman Sumo Friend
BIOINFORMATICS RESEARCH AND APPLICATIONS, ISBRA 2018, 2018, 10847 : 179 - 184
[32] Discovery of Two GSK3β Inhibitors from Sophora flavescens Ait. using Structure-based Virtual Screening and Bioactivity Evaluation
Pan, Dabo
Zeng, Yong
Jiang, Dewen
Zhang, Yonghao
Wu, Mingkai
Huang, Yaxuan
Han, Minzhen
Jin, Xiaojie
CURRENT COMPUTER-AIDED DRUG DESIGN, 2024,
[33] Discovery of novel and highly potential inhibitors of glycogen synthase kinase 3-beta (GSK-3β) through structure-based pharmacophore modeling, virtual computational screening, docking and in silico ADMET analysis
Benghanem, Soumia
Mesli, Fouzia
Zohra, Hadjadj Aoul Fatima
Nacereddine, Chaida
Hadjer, Chenaffa
Abdellatif, Merzoug
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, 2024, 42 (14) : 7091 - 7106

← 1 2 3 4 →