Structures of the σ2 receptor enable docking for bioactive ligand discovery

Abstract

The σ2 receptor has attracted intense interest in cancer imaging1, psychiatric disease2, neuropathic pain3–5, and other areas of biology6,7. 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. 127 new chemotypes with affinities superior to 1 μM were identified, 31 of which had affinities superior to 50 nM. Hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, achieving affinities ranging from 3 to 48 nM with up to 250-fold selectivity versus the σ1 receptor. Crystal structures of two new 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 neuropathic pain model. All three ligands demonstrated time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model9, supporting a role for the σ2 receptor in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes to study under-explored areas of biology using structure-based screens of diverse, ultra-large libraries.