Structure-Based Discovery of Mouse Trace Amine-Associated Receptor 5 Antagonists

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Trace amine-associated receptors (TAARs) are G protein-coupled receptors (GPCRs). Most TAARs, excluding TAAR1, were initially thought to function solely in olfactory perception of volatile amines.
• Many TAARs, particularly TAAR5, remain orphan receptors, lacking identified ligands, despite their nonolfactory expression and therapeutic potential.

Purpose of the Study:

• To identify novel antagonists for TAAR5, a GPCR with therapeutic implications.
• To develop a computational strategy for identifying TAAR5 ligands, leveraging existing knowledge of related receptors.

Main Methods:

• High-throughput screening (HTS) to identify initial TAAR5 antagonists.
• Structure-based virtual screening protocol development and application.
• Homology modeling and comparative analyses of serotonin receptors to model the TAAR5 binding site.

Main Results:

• Identification of four novel TAAR5 antagonists via HTS.
• Discovery of three additional TAAR5 antagonists using a structure-based virtual screening approach, achieving a 10% hit rate.
• Successful modeling of the TAAR5 binding site despite the absence of an experimental structure.

Conclusions:

• Seven novel TAAR5 antagonists were identified, serving as potential lead candidates.
• These findings support the development of new therapeutic agents targeting TAAR5 for neurological and psychiatric disorders like depression, anxiety, and neurodegeneration.