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 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 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-fo

SUBMITTER: Alon A 

PROVIDER: S-EPMC8867396 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature