title: Potent and novel 11β-HSD1 inhibitors identified from shape and docking based virtual screening.
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.
authors.affiliation: Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd, 898 Ha Lei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Xia
authors.forename: Mengzhu
authors.initials: M
authors.lastname: Xue
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Yu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Jianfa
authors.initials: J
authors.lastname: Wang
authors.forename: Yanlian
authors.initials: Y
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D016208:Databases, Factual; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human