Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum

doi:10.1016/j.bmc.2011.09.039

	Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum
	Grienke, Ulrike 5,6; Mihaly-Bison, Judit 1; Schuster, Daniela 3,5; Afonyushkin, Taras 1; Binder, Markus 1; Guan, Shu-hong4 ; Cheng, Chun-ru 4; Wolber, Gerhard 2; Stuppner, Hermann 5,6; Guo, De-an4
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2011-11-15
卷号	19 期号:22 页码:6779-6791
关键词	Farnesoid X receptor Ganoderma lucidum Lanostane triterpenes Ganoderic acids Molecular modeling Virtual screening Natural products
ISSN号	0968-0896
DOI	10.1016/j.bmc.2011.09.039
文献子类	Article
英文摘要	The farnesoid X receptor (FXR) belonging to the metabolic subfamily of nuclear receptors is a ligand-induced transcriptional activator. Its central function is the physiological maintenance of bile acid homeostasis including the regulation of glucose and lipid metabolism. Accessible structural information about its ligand-binding domain renders FXR an attractive target for in silico approaches. Integrated to natural product research these computational tools assist to find novel bioactive compounds showing beneficial effects in prevention and treatment of, for example, the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. Virtual screening experiments of our in-house Chinese Herbal Medicine database with structure-based pharmacophore models, previously generated and validated, revealed mainly lanostane-type triterpenes of the TCM fungus Ganoderma lucidum Karst. as putative FXR ligands. To verify the prediction of the in silico approach, two Ganoderma fruit body extracts and compounds isolated thereof were pharmacologically investigated. Pronounced FXR-inducing effects were observed for the extracts at a concentration of 100 mu g/mL. Intriguingly, five lanostanes out of 25 secondary metabolites from G. lucidum, that is, ergosterol peroxide (2), lucidumol A (11), ganoderic acid TR (12), ganodermanontriol (13), and ganoderiol F (14), dose-dependently induced FXR in the low micromolar range in a reporter gene assay. To rationalize the binding interactions, additional pharmacophore profiling and molecular docking studies were performed, which allowed establishing a first structure-activity relationship of the investigated triterpenes. (C) 2011 Elsevier Ltd. All rights reserved.
资助项目	National Research Network (NFN)[S10703/S10711/S10713] ; Austrian Science Fund (FWF)[00000000] ; University of Innsbruck[00000000]
WOS关键词	FARNESOID-X-RECEPTOR ; BILE-ACID RECEPTOR ; NATURAL-PRODUCT GUGGULSTERONE ; ORPHAN NUCLEAR RECEPTOR ; HYPERLIPIDEMIC RATS ; GENE-EXPRESSION ; MARINE SPONGE ; POTENT ; LIGAND ; ACTIVATION
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000296535900028
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278335]
专题	成果转移转化处上海中药现代化研究中心
通讯作者	Rollinger, Judith M.
作者单位	1.Med Univ Vienna, Ctr Biomol Med & Pharmacol, Dept Vasc Biol & Thrombosis Res, A-1090 Vienna, Austria; 2.Free Univ Berlin, Inst Pharm Pharmaceut Chem, D-14195 Berlin, Germany 3.Univ Innsbruck, Comp Aided Mol Design Grp, Inst Pharm Pharmaceut Chem, A-6020 Innsbruck, Austria; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 5.Univ Innsbruck, Ctr Mol Biosci Innsbruck, A-6020 Innsbruck, Austria; 6.Univ Innsbruck, Inst Pharm Pharmacognosy, A-6020 Innsbruck, Austria;
推荐引用方式 GB/T 7714	Grienke, Ulrike,Mihaly-Bison, Judit,Schuster, Daniela,et al. Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2011,19(22):6779-6791.
APA	Grienke, Ulrike.,Mihaly-Bison, Judit.,Schuster, Daniela.,Afonyushkin, Taras.,Binder, Markus.,...&Rollinger, Judith M..(2011).Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum.BIOORGANIC & MEDICINAL CHEMISTRY,19(22),6779-6791.
MLA	Grienke, Ulrike,et al."Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum".BIOORGANIC & MEDICINAL CHEMISTRY 19.22(2011):6779-6791.