Discovery of Fluorescent Probe ABDS-2 for Farnesoid X Receptor Modulator Characterization and Cell-Based Imaging

Area of Science:

• Pharmacology
• Molecular Biology
• Biochemistry

Background:

• Farnesoid X receptor (FXR) is crucial for bile acid and lipid metabolism, presenting a key drug discovery target.
• Overactivation of FXR can cause adverse effects, necessitating precise monitoring tools.
• Existing methods for studying FXR may lack the sensitivity or real-time capabilities required for detailed cellular analysis.

Purpose of the Study:

• To design and develop a novel fluorescent probe for monitoring FXR activity.
• To optimize probe design using computer-aided drug design (CADD) for enhanced sensitivity and stability.
• To validate the probe's utility in biochemical assays and cellular bioimaging for FXR homeostasis.

Main Methods:

• Computer-aided drug design (CADD) was employed to optimize linker strategies for fluorescent probes.
• Molecular dynamics simulations were used to assess probe designs.
• Selected probes were synthesized and evaluated through in vitro biochemical assays and high-throughput screening.

Main Results:

• A novel fluorescent probe, ABDS-2, was successfully developed and synthesized.
• ABDS-2 demonstrated high sensitivity, stability, and satisfactory validation in high-throughput screening.
• The probe enabled real-time, cellular-level bioimaging of FXR homeostasis, offering spatially resolved insights.

Conclusions:

• CADD is an efficient approach for designing functional chemical probes.
• ABDS-2 serves as a valuable tool for in vitro assays and cellular imaging of FXR.
• This probe facilitates deeper understanding of molecular interactions critical for cellular function and FXR homeostasis.