Structures of the σ2 receptor enable docking for bioactive ligand discovery

Assaf Alon, Jiankun Lyu, Joao M. Braz, Tia A. Tummino, Veronica Craik, Matthew J. O’Meara, Chase M. Webb, Dmytro S. Radchenko, Yurii S. Moroz, Xi-Ping Huang, Yongfeng Liu, Bryan L. Roth, John J. Irwin, Allan I. Basbaum (), Brian K. Shoichet () and Andrew C. Kruse ()
Additional contact information
Assaf Alon: Harvard Medical School
Jiankun Lyu: University of California, San Francisco
Joao M. Braz: University of California, San Francisco
Tia A. Tummino: University of California, San Francisco
Veronica Craik: University of California, San Francisco
Matthew J. O’Meara: University of Michigan
Chase M. Webb: University of California, San Francisco
Dmytro S. Radchenko: Enamine
Yurii S. Moroz: Chemspace
Xi-Ping Huang: University of North Carolina at Chapel Hill School of Medicine
Yongfeng Liu: University of North Carolina at Chapel Hill School of Medicine
Bryan L. Roth: University of North Carolina at Chapel Hill School of Medicine
John J. Irwin: University of California, San Francisco
Allan I. Basbaum: University of California, San Francisco
Brian K. Shoichet: University of California, San Francisco
Andrew C. Kruse: Harvard Medical School

Nature, 2021, vol. 600, issue 7890, 759-764

Abstract: Abstract 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 through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology.

Date: 2021
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DOI: 10.1038/s41586-021-04175-x

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