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DOI: 10.1055/s-0031-1282129
In silico approaches to identify FXR-inducing constituents from Ganoderma lucidum - the Chinese mushroom of immortality
The ligand-dependent transcription factor farnesoid X receptor (FXR), belonging to the nuclear receptor superfamily, plays a regulative role in glucose and lipid metabolism. Due to its revealed structural information FXR represents an attractive target for computer-aided drug design. Pharmacophore models based on publicly accessible FXR crystal structures were generated as in silico tools to identify novel bioactive compounds with the ability to control endogenous pathways in close relation to inflammatory diseases, like metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes [1, 2]. Lanostane-type triterpenes, as typically found in the fruit body of the famous TCM fungus Ganoderma lucidum (Curtis) P. Karst (Ganodermataceae) were identified as putative FXR ligands by virtual screening of our in-house Chinese Herbal Medicine database [3].
To verify the in silico predictions, 25 constituents isolated from G. lucidum were tested on their FXR-inducing potential in a reporter gene assay at 10µM. A dose-dependent activity could be confirmed for five lanostane triterpenes, i.e. ergosterol peroxide, lucidumol A, ganoderic acid TR, ganodermanontriol, and ganoderiol F, with EC50 values between 1µM and 30µM [4]. In depth structural insights were gained by molecular docking studies allowing a first structure activity relationship. Furthermore the five active compounds were tested for general anti-inflammatory effects. At a test concentration of 5µM they significantly inhibited the TNF or LPS induced expression of IL-8 and E-selectin in human endothelial cells [4]. The observed FXR induction indicates a possible involvement of this nuclear receptor in the mechanism of the inflammatory regulation by these compounds.
Keywords: farnesoid X receptor, Ganoderma lucidum, lanostane triterpenes, molecular modeling, virtual screening, natural products
Acknowledgement: This work was supported by the National Research Network (NFN) – project „Drugs from Nature Targeting Inflammation“ S10703/S10711/S10713 granted by the Austrian Science Fund (FWF).
References: 1. Schuster D et al. (2011) submitted.
2. Lin H R et al. (2006) Bioorg Med Chem Lett 16: 4178.
3. Fakhrudin N et al. (2010) Mol Pharmacol 77: 559.
4. Grienke U et al. (2011) submitted.