Virtual screening

Ligand (biochemistry)

Selectivity

Biotechnology

Receptor

In vivo

Combinatorial chemistry

Stereochemistry

Biology

Nursing

Catalysis

Ligand efficiency

Chemistry

In vitro

Neuropathic pain

Affinities

Potency

Drug discovery

Binding affinities

Docking (animal)

Biochemistry

Medicine

Pharmacology

Nature

The σ2 receptor has attracted intense interest in cancer imaging1, psychiatric disease2, neuropathic pain3–5 and other areas of biology6,7. Here we determined the crystal structure of this receptor in complex with the clinical candidate roluperidone2 and the tool compound PB288. These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. We identified 127 new chemotypes with affinities superior to 1 μM, 31 of which had affinities superior to 50 nM. The hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, and achieved affinities that ranged from 3 to 48 nM, with up to 250-fold selectivity versus the σ1 receptor. Crystal structures of two ligands bound to the σ2 receptor confirmed the docked poses. To investigate the contribution of the σ2 receptor in pain, two potent σ2-selective ligands and one potent σ1/σ2 non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model9, suggesting that the σ2 receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes&nbsp;through structure-based screens of ultra large libraries, enabling study of&nbsp;underexplored areas of biology. Crystal structures of the σ2 receptor are determined and used to perform a docking screen of nearly 500 million molecules, identifying σ2-selective ligands and providing insight into the role of σ2 in neuropathic pain.

Structures of the σ2 receptor enable docking for bioactive ligand discovery