Structures of the σ₂ receptor enable docking for bioactive ligand discovery

Area of Science:

• Pharmacology and Structural Biology
• Neuroscience

Background:

• The sigma-2 receptor is a key target in cancer imaging, psychiatric disorders, and neuropathic pain.
• Understanding sigma-2 receptor interactions is crucial for developing targeted therapeutics.

Purpose of the Study:

• To determine the crystal structure of the sigma-2 receptor in complex with known ligands.
• To utilize these structures for large-scale virtual screening to identify novel chemotypes.
• To investigate the role of the sigma-2 receptor in neuropathic pain.

Main Methods:

• Crystal structure determination of the sigma-2 receptor with roluperidone and PB28.
• Large-scale virtual screening of 490 million compounds.
• Synthesis and affinity testing of 484 compounds.
• Optimization of hit compounds for potency and selectivity.
• In vivo efficacy testing in a mouse model of neuropathic pain.

Main Results:

• Identified 127 new chemotypes with affinities >1 µM, including 31 with affinities >50 nM.
• Optimized three compounds with affinities from 3 to 48 nM and up to 250-fold selectivity over sigma-1 receptor.
• Demonstrated that potent sigma-2 ligands reduce mechanical hypersensitivity in a neuropathic pain model.
• Confirmed docked poses through co-crystal structures of two ligands bound to the sigma-2 receptor.

Conclusions:

• Structure-based screening of ultra-large libraries enables rapid discovery of in vivo probes.
• The sigma-2 receptor plays a significant role in nociception.
• This approach facilitates the study of underexplored biological targets.