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; Andrew C Kruse

doi:10.1038/s41586-021-04175-x

Structures of the σ₂ receptor enable docking for bioactive ligand discovery

Nature. 2021 Dec;600(7890):759-764. doi: 10.1038/s41586-021-04175-x. Epub 2021 Dec 8.

Authors

Assaf Alon^#¹, Jiankun Lyu^#², Joao M Braz^#³, Tia A Tummino^{2

4}, Veronica Craik³, Matthew J O'Meara⁵, Chase M Webb^{2

4}, Dmytro S Radchenko^{6

7}, Yurii S Moroz⁸, Xi-Ping Huang^{9

10}, Yongfeng Liu^{9

10}, Bryan L Roth^{9

10

11}, John J Irwin², Allan I Basbaum¹², Brian K Shoichet¹³, Andrew C Kruse¹⁴

Affiliations

¹ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
² Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
⁴ Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁶ Enamine, Kyiv, Ukraine.
⁷ Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
⁸ Chemspace, Kyiv, Ukraine.
⁹ Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
¹⁰ National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
¹¹ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. [email protected].
¹³ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA. [email protected].
¹⁴ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. [email protected].

^# Contributed equally.

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-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.

MeSH terms

Animals
Ligands
Mice
Neuralgia* / drug therapy
Receptors, sigma* / metabolism
Structure-Activity Relationship

Substances

Ligands
Receptors, sigma

Abstract

MeSH terms

Substances

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