Abstract
Agonists of liver X receptors (LXR) α and β are important regulators of cholesterol metabolism, but agonism of the LXRα subtype appears to cause hepatic lipogenesis, suggesting LXRβ-selective activators are attractive new lipid lowering drugs. In this work, pharmacophore modeling and shape-based virtual screening were combined to predict new LXRβ-selective ligands. Out of the 10 predicted compounds, three displayed significant LXR activity. Two activated both LXR subtypes. The third compound activated LXRβ 1.8-fold over LXRα.
Highlights
The liver X receptors (LXRα and LXRβ) belong to the nuclear receptor superfamily and are key regulators of cholesterol homeostasis and reverse cholesterol transport (RCT).[7−9] LXRα is highly expressed in metabolically active tissues, such as liver, intestine, adipose tissue, and macrophages, whereas LXRβ is ubiquitously expressed
Despite the antiatherosclerotic properties of LXR agonists, their use as therapeutic agents has been hampered by unfavorable side effects of LXR stimulation, such as increased hepatic lipogenesis, hypertriglyceridemia and liver steatosis.[15,16]
These adverse effects are attributed to LXRα, which is the predominant LXR subtype in the liver inducing the expression of genes involved in fatty acid and triglyceride synthesis.[17,18]
Summary
Letter change during the screening optimizing its fitting into the model. Two models were not able to find any compounds from the data set and were discarded. To increase the chance of finding a LXRβselective hit, a shape-based rapid overlay of chemical structures (ROCS)[23] screening was performed.[24] The most selective agonist from the Molteni series (compound 1, EC50(LXRβ) = 0.25 μM, not active on LXR-α) was used as a ROCS shape query (Figure 2). In this method, a low energy 3D conformer of a compound is calculated, and a shape is derived from the molecule’s surface.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
