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

[21]

TANNIN GM, 1991, J BIOL CHEM, V266, P16653

[22] Glucocorticoid antagonism limits adiposity rebound and glucose intolerance in young male rats following the cessation of daily exercise and caloric restriction [J].

Teich, Trevor ;

Dunford, Emily C. ;

Porras, Deanna P. ;

Pivovarov, Jacklyn A. ;

Beaudry, Jacqueline L. ;

Hunt, Hazel ;

Belanoff, Joseph K. ;

Riddell, Michael C. .

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2016, 311 (01) :E56-E68

[23] The functional consequences of IIβ-hydroxysteroid dehydrogenase expression in adipose tissue [J].

Tomlinson, JW ;

Stewart, PM .

HORMONE AND METABOLIC RESEARCH, 2002, 34 (11-12) :746-751

[24] Beneficial Effects of Corn Silk on Metabolic Syndrome [J].

Wang, Bing ;

Xiao, Tiegang ;

Ruan, Jun ;

Liu, Wensheng .

CURRENT PHARMACEUTICAL DESIGN, 2017, 23 (34) :5097-5103

[25] Information Structure Influences Depth of Syntactic Processing: Event-Related Potential Evidence for the Chomsky Illusion [J].

Wang, Lin ;

Bastiaansen, Marcel ;

Yang, Yufang ;

Hagoort, Peter .

PLOS ONE, 2012, 7 (10)

[26]

Wang Mengmeng, 2011, Drug Metab Lett, V5, P55, DOI 10.2174/187231211794455280

[27] Synthesis and biological evaluation of heterocycle containing adamantane 11β-HSD1 inhibitors [J].

Yeh, Vince S. C. ;

Patel, Jyoti R. ;

Yong, Hong ;

Kurukulasuriya, Ravi ;

Fung, Steven ;

Monzon, Katina ;

Chiou, William ;

Wang, Jiahong ;

Stolarik, Deanne ;

Imade, Hovis ;

Beno, David ;

Brune, Michael ;

Jacobson, Peer ;

Sham, Hing ;

Link, J. T. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (20) :5414-5419

[28] The discovery of 2-anilinothiazolones as 11β-HSD1 inhibitors [J].

Yuan, Chester ;

St. Jean, David J., Jr. ;

Liu, Qingyian ;

Cai, Lynn ;

Li, Aiwen ;

Han, Nianhe ;

Moniz, George ;

Askew, Ben ;

Hungate, Randall W. ;

Johansson, Lars ;

Tedenborg, Lars ;

Pyring, David ;

Williams, Meredith ;

Hale, Clarence ;

Chen, Michelle ;

Cupples, Rod ;

Zhang, Jiandong ;

Jordan, Steven ;

Bartberger, Michael D. ;

Sun, Yaxiong ;

Emery, Maurice ;

Wang, Minghan ;

Fotsch, Christopher .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (22) :6056-6061

[29] The 11β-hydroxysteroid dehydrogenase type 1 inhibitor protects against the insulin resistance and hepatic steatosis in db/db mice [J].

Yuan, Xiaohuan ;

Li, Hongzhi ;

Bai, He ;

Zhao, Xiaojin ;

Zhang, Chunlei ;

Liu, Haifeng ;

Zhang, Yufei ;

Zhao, Binghai ;

Wu, Yan ;

Liu, Jieting ;

Xiang, Qi ;

Feng, Biao ;

Chu, Yanhui ;

Huang, Yadong .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2016, 788 :140-151

[30] Synthesis of novel curcumin analogues for inhibition of 11β-hydroxysteroid dehydrogenase type 1 with anti-diabetic properties [J].

Yuan, Xiaohuan ;

Li, Hongzhi ;

Bai, He ;

Su, Zhijian ;

Xiang, Qi ;

Wang, Chaonan ;

Zhao, Binghai ;

Zhang, Yufei ;

Zhang, Qihao ;

Chu, Yanhui ;

Huang, Yadong .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2014, 77 :223-230

← 1 2 3 4 →