GPR3 Ligands Discovered through Combined Virtual and Conformational Biosensor-Based Screening

Area of Science:

• Pharmacology
• Biochemistry
• Neuroscience

Background:

• G protein-coupled receptor 3 (GPR3) is implicated in physiological processes like energy expenditure and Alzheimer's disease pathology.
• The therapeutic potential of GPR3 ligands is hindered by a lack of suitable screening technologies and drug-like compounds.
• Existing screening methods (cAMP, β-arrestin) are insufficient for effective GPR3 drug discovery.

Purpose of the Study:

• To develop an innovative screening technology for GPR3 drug discovery.
• To identify novel GPR3 ligands with therapeutic potential.
• To establish a versatile biosensor platform for orphan G protein-coupled receptors (GPCRs).

Main Methods:

• Development of a conformational GPR3 biosensor for high-throughput screening (HTS).
• Virtual compound screening using GPR3 homology models.
• Classical medicinal chemistry for ligand optimization.

Main Results:

• A novel, HTS-compatible conformational GPR3 biosensor was successfully developed.
• Identification of new GPR3 ligands, including compound 33.
• Compound 33 demonstrated nanomolar potency in modulating GPR3-dependent Gs activity.

Conclusions:

• The developed GPR3 biosensor overcomes limitations of conventional screening methods.
• Novel GPR3 ligands were identified, offering a foundation for future drug development.
• The biosensor approach serves as a model for discovering ligands for other challenging orphan GPCRs.