Potent and novel 11β-HSD1 inhibitors identified from shape and docking based virtual screening

Guangxin Xia; Mengzhu Xue; Lin Liu; Jianxin Yu; Haiyan Liu; Ping Li; Jianfa Wang; Yanlian Li; Bing Xiong; Jingkang Shen

doi:10.1016/j.bmcl.2011.08.019

Potent and novel 11β-HSD1 inhibitors identified from shape and docking based virtual screening

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5739-44. doi: 10.1016/j.bmcl.2011.08.019. Epub 2011 Aug 8.

Authors

Guangxin Xia¹, Mengzhu Xue, Lin Liu, Jianxin Yu, Haiyan Liu, Ping Li, Jianfa Wang, Yanlian Li, Bing Xiong, Jingkang Shen

Affiliation

¹ Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd, 898 Ha Lei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.

PMID: 21873057
DOI: 10.1016/j.bmcl.2011.08.019

Abstract

Several potent and novel 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors were discovered from in silico screening the commercially available Maybridge database. Among them, seven hit compounds showed good affinity, with IC(50) values lower than 100 nM and the best one 3.7 nM. To select the lead for further optimization, computational ADME/T prediction, the CYP3A4 inhibition and 11β-HSD1 over 11β-HSD2 selectivity test were also performed. Taking all of the above factors into consideration, two promising compounds were selected as lead structures for further development. The employed hierarchical virtual screening protocol not only demonstrates its efficiency, but also provides novel and selective compounds for developing 11β-HSD1 inhibitors to protect against metabolic syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 2 / genetics
11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
Animals
Computer Simulation
Cytochrome P-450 CYP3A / metabolism
Cytochrome P-450 CYP3A Inhibitors
Databases, Factual
Drug Design*
Drug Discovery / methods*
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology
HEK293 Cells
High-Throughput Screening Assays
Humans
Inhibitory Concentration 50
Metabolic Syndrome / drug therapy
Metabolic Syndrome / pathology
Metabolic Syndrome / prevention & control*
Mice
Models, Molecular
Structure-Activity Relationship

Substances

Cytochrome P-450 CYP3A Inhibitors
Enzyme Inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 1
11-beta-Hydroxysteroid Dehydrogenase Type 2
Cytochrome P-450 CYP3A
CYP3A4 protein, human