Structures of the σ2 receptor enable docking for bioactive ligand discovery

Autor: 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, Andrew C. Kruse
Rok vydání: 2021
Předmět:
Zdroj: Nature
Nature, vol 600, iss 7890
ISSN: 1476-4687
0028-0836
Popis: The σ(2) receptor has attracted intense interest in cancer imaging(1), psychiatric disease(2), neuropathic pain(3–5), and other areas of biology(6,7). 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. 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 σ(1) receptor. Crystal structures of two new ligands bound to the σ(2) receptor confirmed the docked poses. To investigate the contribution of the σ(2) receptor in pain, two potent σ(2)-selective ligands and one potent σ(1)/σ(2) 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 model(9), supporting a role for the σ(2) 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.
Databáze: OpenAIRE
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