Discovery of new FXR agonists based on 6-ECDCA binding properties by virtual screening and molecular docking

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• The Farnesoid X Receptor (FXR) is a nuclear receptor regulating bile acid, lipid, and glucose metabolism.
• FXR agonists are used to treat metabolic diseases like cholestasis and hepatic disorders.
• Expanding the library of FXR agonists is crucial for developing new therapeutics.

Purpose of the Study:

• To discover novel FXR agonists using a structure-based pharmacophore and docking screening protocol.
• To identify small molecules with potent FXR-activating properties.
• To expand the chemical pool of FXR modulators for therapeutic applications.

Main Methods:

• Utilized a structure-based pharmacophore and docking screening protocol to identify potential FXR agonists.
• Screened a large database of commercial chemicals.
• Conducted experimental assays to validate FXR activation by selected molecules.

Main Results:

• Screened a large chemical database, selecting 25 candidate molecules.
• Identified three novel FXR agonists.
• Discovered one full agonist more potent than chenodeoxycholic acid and two partial agonists.

Conclusions:

• The study successfully identified novel FXR agonists through computational screening and experimental validation.
• The newly discovered agonists, particularly the potent full agonist, offer promising therapeutic leads for metabolic and liver diseases.
• This work expands the available FXR-targeting small molecules, paving the way for new treatment strategies.