Accelerating the orphan GPCR pipeline: GPR149 as a case study in dual-domain target validation

Area of Science:

• Pharmacology
• Neuroscience
• Biochemistry

Background:

• Drug development for central nervous system (CNS) and metabolic diseases has high failure rates, often due to poor understanding of drug targets.
• Orphan G-protein-coupled receptors (GPCRs) with unknown ligand chemistry present significant risks but also high rewards in pharmaceutical development.

Purpose of the Study:

• To present a framework for de-risking orphan GPCR targets in drug development.
• To utilize GPR149 as a prototype to demonstrate the framework's efficacy.

Main Methods:

• The Four-Pillar Framework was employed, integrating high-throughput screening, cryo-electron microscopy (EM), artificial intelligence (AI)-driven chemistry, and parallel circuit validation.
• GPR149 was used as a model orphan receptor to test the methodology.

Main Results:

• The framework successfully identified dual therapeutic applications for GPR149 in metabolic (weight loss) and CNS disorders.
• A previously intractable orphan receptor was transformed into a promising development asset.

Conclusions:

• The Four-Pillar Framework provides a reproducible method for exploring orphan GPCRs, including the 'dark GPCRome'.
• This approach is particularly relevant for complex disorders with co-presenting metabolic and CNS comorbidities.