11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Development by Lentiviral Screening Based on Computational Modeling

被引：5

作者：

Liu, Haifeng ^{[1
]}

Li, Lingyu ^{[1
]}

Zhang, Chunlei ^{[1
]}

Li, Hongzhi ^{[1
]}

Liu, Jieting ^{[1
]}

Tang, Chunyin ^{[1
]}

Zhang, Yufei ^{[1
]}

Wu, Dan ^{[1
]}

Chu, Yanhui ^{[1
]}

Wu, Yan ^{[1
]}

Yuan, Xiaohuan ^{[1
]}

机构：

[1] Mudanjiang Med Univ, Heilongjiang Key Lab Antifibrosis Biotherapy, Mudanjiang 157011, Peoples R China

来源：

PHARMACOLOGY | 2018年 / 102卷 / 3-4期

关键词：

11 beta-Hydroxysteroid dehydrogenase type 1; Screening; Recombinant plasmids; Lentiviral transduction; Computational modeling; 11-BETA-HSD1; DISCOVERY; OBESITY;

D O I：

10.1159/000491397

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

In this study, rat and human 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) have been cloned by lentiviral transduction and expressed by CHO-K1 cells. The results showed that recombinant plasmids contained R11bhsd1orH11bhsd1 have been constructed, which is consistent with the gene bank respectively. A clone cell was selected with G418 and cultivated to express 11 beta-HSD1. 11 beta-HSD1 catalytic activity of rat and human were 99.5 and 98.7%, respectively, determined by scanning radiometer. And the cloned CHO-K1 cells expressed the protein of 11 beta-HSD1 in a long-term and stable manner, which makes it suitable for screening 11 beta-HSD1 inhibitor. The three-dimensional structure of 11 beta-HSD1 was used for studying the interaction between inhibitor and enzyme by the binding poses predicted by AutoDock and LeDock software. The docking results revealed that compound 8 forms 2 hydrogen bonds with the residues of Gly-216 and Ile-218 in 11 beta-HSD1, that is to say compound 8 maybe a good 11 beta-HSD1 inhibitor. Moreover, C57BL/6 mice with R11bHsd1 overexpression had a higher body weight, glucose, total cholesterol, and triglyceride levels compared to the mice treated with an empty viral vector. The results might provide a beneficial foundation for selecting inhibitors of 11 beta-HSD1 or for researching drug candidate mechanisms. (C) 2018 S. Karger AG, Basel

引用

页码：169 / 179

页数：11

共 31 条

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