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Publication Abstract from PubMed

The sigma2 receptor has attracted intense interest in cancer imaging(1), psychiatric disease(2), neuropathic pain(3-5) and other areas of biology(6,7). Here we determined the crystal structure of this receptor in complex with the clinical candidate roluperidone(2) and the tool compound PB28(8). 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 muM, 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 sigma1 receptor. Crystal structures of two ligands bound to the sigma2 receptor confirmed the docked poses. To investigate the contribution of the sigma2 receptor in pain, two potent sigma2-selective ligands and one potent sigma1/sigma2 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 model(9), suggesting that the sigma2 receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology.

Structures of the sigma2 receptor enable docking for bioactive ligand discovery.,Alon A, Lyu J, Braz JM, Tummino TA, Craik V, O'Meara MJ, Webb CM, Radchenko DS, Moroz YS, Huang XP, Liu Y, Roth BL, Irwin JJ, Basbaum AI, Shoichet BK, Kruse AC Nature. 2021 Dec 8. pii: 10.1038/s41586-021-04175-x. doi:, 10.1038/s41586-021-04175-x. PMID:34880501^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.