Discovery of New Liver X Receptor Agonists by Pharmacophore Modeling and Shape-Based Virtual Screening

Agonists of liver X receptors (LXR) alpha and beta are important regulators of cholesterol metabolism, but agonism of the LXR alpha subtype appears to cause hepatic lipogenesis, suggesting LXR beta-selective activators are attractive new lipid lowering drugs. In this work, pharmacophore modeling and shape-based virtual screening were combined to predict new LXR beta-selective ligands. Out of the 10 predicted compounds, three displayed significant LXR activity. Two activated both LXR subtypes. The third compound activated LXR beta 1.8-fold over LXR alpha.