Modeling and Deorphanization of Orphan GPCRs

Area of Science:

• Pharmacology
• Computational Chemistry
• Structural Biology

Background:

• Approximately 120 G protein-coupled receptors (GPCRs) are classified as 'orphan', meaning their functions and disease relevance are largely unknown.
• Orphan GPCRs represent significant opportunities for novel drug discovery and treating unmet medical needs.

Purpose of the Study:

• To describe the application of molecular modeling and virtual screening for discovering surrogate ligands for orphan GPCRs.
• To demonstrate the utility of these computational methods in elucidating orphan GPCR functions and identifying potential drug candidates.

Main Methods:

• Utilized molecular modeling to build active structural models of orphan GPCRs, leveraging data from constitutively active mutants and published active structures.
• Employed virtual screening of compound libraries against these models to identify potential synthetic surrogate ligands.

Main Results:

• Successfully applied the described molecular modeling and virtual screening workflow to identify surrogate ligands.
• Provided specific examples of successful ligand discovery for a simulated orphan GPCR (CCKA) and two actual orphan GPCRs (GPR52 and GPR34).

Conclusions:

• Molecular modeling and virtual screening are efficient complementary approaches to experimental methods for orphan GPCR research.
• The identified surrogate ligands can aid in understanding the physiological roles of orphan GPCRs and their potential as therapeutic targets.