18 research outputs found
Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis
Background: The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite
FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver
diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury
caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from
the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated
genes and biological functions.
Principal Findings: Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation
assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of
human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and
thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic
FXR agonists on FXR-regulated genes, including SHP, OSTa, BSEP and MRP4. A proof-of-concept study carried out to
investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model
of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by
assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in
bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a
basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed
to rescue from liver injury and downregulated the expression of MRP4.
Conclusions: FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible
strategy to target obstructive cholestasis
Combining self- and cross-docking as benchmark tools: the performance of DockBench in the D3R Grand Challenge 2
Abstract
Molecular docking is a powerful tool in the field of computer-aided molecular design. In particular, it is the technique of choice for the prediction of a ligand pose within its target binding site. A multitude of docking methods is available nowadays, whose performance may vary depending on the data set. Therefore, some non-trivial choices should be made before starting a docking simulation. In the same framework, the selection of the target structure to use could be challenging, since the number of available experimental structures is increasing. Both issues have been explored within this work. The pose prediction of a pool of 36 compounds provided by D3R Grand Challenge 2 organizers was preceded by a pipeline to choose the best protein/docking-method couple for each blind ligand. An integrated benchmark approach including ligand shape comparison and cross-docking evaluations was implemented inside our DockBench software. The results are encouraging and show that bringing attention to the choice of the docking simulation fundamental components improves the results of the binding mode predictions
Structural Insight into the Binding Mode of FXR and GPBAR1 Modulators
In this chapter we provide an exhaustive overview of the binding modes of bile acid (BA) and non-BA ligands to the nuclear farnesoid X receptor (FXR) and the G-protein bile acid receptor 1 (GPBAR1). These two receptors play a key role in many diseases related to lipid and glucose disorders, thus representing promising pharmacological targets. We pay particular attention to the chemical and structural features of the ligand-receptor interaction, providing guidelines to achieve ligands endowed with selective or dual activity towards the receptor and paving the way to future drug design studies