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

• Published in: Bioorganic & medicinal chemistry 2011-11, Vol.19 (22), p.6779-6791
• Main Authors: Grienke, Ulrike, Mihály-Bison, Judit, Schuster, Daniela, Afonyushkin, Taras, Binder, Markus, Guan, Shu-hong, Cheng, Chun-ru, Wolber, Gerhard, Stuppner, Hermann, Guo, De-an, Bochkov, Valery N., Rollinger, Judith M.
• Format: Article
• Language: English
• Subjects: Animals; atherosclerosis; bile acids; bioactive properties; Biological and medical sciences; ergosterol; Farnesoid X receptor; fruiting bodies; fungi; Ganoderic acids; Ganoderma; Ganoderma lucidum; General pharmacology; glucose; HEK293 Cells; Hep G2 Cells; herbal medicines; homeostasis; Humans; hyperlipidemia; Lanostane triterpenes; lipid metabolism; Medical sciences; metabolic syndrome; Mice; Molecular modeling; Natural products; noninsulin-dependent diabetes mellitus; Pharmacognosy. Homeopathy. Health food; pharmacology; Pharmacology. Drug treatments; prediction; receptors; Receptors, Cytoplasmic and Nuclear - agonists; Reishi - chemistry; reporter genes; screening; secondary metabolites; Stereoisomerism; Structure-Activity Relationship; structure-activity relationships; transcription factors; Triterpenes - isolation & purification; Triterpenes - pharmacology; triterpenoids; Virtual screening
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.09.039

Graphical abstract 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 100μg/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.