Identify liver X receptor β modulator building blocks by developing a fluorescence polarization-based competition...

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Drug Discovery

Background:

• Liver X receptors (LXRs) are key regulators of lipid metabolism and inflammation, making them attractive therapeutic targets for various diseases.
• Current LXR modulators are limited, highlighting the need for novel drug discovery approaches.
• Fragment-based lead discovery (FBLD) offers a powerful strategy for identifying new drug scaffolds, but its application to LXRs is underexplored.

Purpose of the Study:

• To develop a specific fragment screening method for the dynamic and hydrophobic ligand-binding domain (LBD) of LXRs.
• To identify novel LXRβ binding fragments using FBLD.
• To provide a foundation for developing new LXRβ modulators.

Main Methods:

• Design and synthesis of fluorescent tracers for LXRβ ligand binding detection.
• Development of a fluorescence polarization assay for fragment screening.
• Screening of 1074 fragments against LXRβ-LBD.
• Validation of fragment hits using co-activator recruitment and reporter gene assays.
• X-ray crystallography to determine the co-crystal structure of LXRβ-LBD with a validated fragment.

Main Results:

• A hyodeoxycholic acid-based fluorescent tracer successfully detected LXRβ ligand binding.
• Screening identified 27 binding fragments out of 1074 tested.
• Co-activator recruitment and reporter gene assays confirmed fragment activity.
• The co-crystal structure of LXRβ-LBD with fragment F3 was solved.

Conclusions:

• A novel, fluorescence-based fragment screening tool for LXRβ was established.
• The identified LXRβ binding fragments represent promising starting points for developing new LXRβ modulators.
• This work lays the groundwork for novel therapeutic strategies targeting LXRβ-related diseases.