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Abstract
Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4,000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method. After the yeast two-hybrid (Y2H) assay, six natural products were identified as FXR antagonists which blocked the CDCA-induced SRC-1 association. The IC50 values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3a, named daphneone with chain scaffold, are as low as 1.29 and 1.79 μM, respectively. Compared to the control compound guggulsterone (IC50 = 6.47 μM), compounds 2a and 3a displayed 5- and 3-fold higher antagonistic activities against FXR, respectively. Remarkably, the two representative compounds shared low topological similarities with other reported FXR antagonists. According to the putative binding poses, the molecular basis of these antagonists against FXR was also elucidated in this report.
Highlights
The farnesoid X receptor (FXR, NR1H4), a member of the metabolic nuclear receptor superfamily, regulates the expressions and activities of a broad spectrum of genes
Previous studies have shown that Farnesoid X receptor (FXR) can be activated by structurally diverse agonists, and an array of crystal structures of FXR-ligand-binding domain (LBD) complexed with agonists have been solved
Given the variability of the binding pockets occupied by distinct modulators, it is necessary to use different FXR crystallographic models in the virtual screening process, in order to maximize the diversity of hit compounds
Summary
The farnesoid X receptor (FXR, NR1H4), a member of the metabolic nuclear receptor superfamily, regulates the expressions and activities of a broad spectrum of genes. FXR is conserved from teleost fish to human beings (Maglich et al, 2003) and is abundantly expressed in liver, intestine, and kidney. FXR is reported to exert regulatory roles in lipoprotein and glucose homeostasis, fatty acid and triglyceride synthesis, liver regeneration, and bacterial growth in the intestine (Lee et al, 2006; Wang et al, 2008). All these accumulating data make FXR a promising pharmaceutical
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