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Structures of the σ2 receptor enable docking for bioactive ligand discovery
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Abstract
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. 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 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 σ 1 receptor. Crystal structures of two 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 model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model 9, suggesting that the σ 2 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.
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“The crystal structure of TMEM97, although bovine, was resolved in 2021 which illuminated the docking sites of small molecule S2R ligands, PB28, and roluperidone [63]”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [63]
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“The ligand binding site described for 20(S)-OHC in this model is remarkably consistent with the ligand-bound crystal structure of S2R, recently reported for S2R in complex with synthetic S2R ligands [63].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [63]
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Self-citation
Metadata
- Authors
- Alon, A., Lyu, J., Braz, J. M., Tummino, T. A., Craik, V., O’Meara, M. J., Webb, C. M., Radchenko, D. S., Moroz, Y. S., Huang, X.-P., Liu, Y., Roth, B. L., Irwin, J. J., Basbaum, A. I., Shoichet, B. K., & Kruse, A. C.
- Affiliations
- Harvard University (US)
- University of California, San Francisco (US)
- University of Michigan (US)
- Taras Shevchenko National University of Kyiv (UA)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Basbaum, Allan I.
- Shoichet, Brian K.
- Kruse, Andrew C.
- ORCID
- Venue
- Nature
- Published
- 2021-12-08
- Volume
- 600
- Issue
- 7890
- Pages
- 759-764
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8867396
- OpenAlex
- W4200289210
- Cited by
- 211
- References
- 92
- Citations by year
- 2026: 24 · 2025: 41 · 2024: 49 · 2023: 55 · 2022: 37 · 2021: 5
- FWCI
- 11.93
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, Contract No. DE-AC02-06CH11357., AC02‐06CH11357, 06CH11357, No. DE-AC02-06CH11357, DE-AC02-)
- Sanofi
- Vallee Foundation
- National Institutes of Health (ACB-12002, 1s10od012289-01a1, DE-AC02–06CH11357, AGM-12006)
- Defense Advanced Research Projects Agency (HR0011, HR0011-19-2-0020)
- Office of Science (Contract No. DE-AC02-06CH11357, AC02‐06CH11357, DE-AC02, No. DE-AC02-06CH11357., 06CH11357, DE-AC02-06CH11357)
- National Cancer Institute (DE-AC02-06CH11357, ACB12002, AGM-12006)
- National Institute of General Medical Sciences (S10 OD012289, R01GM133836, R01GM119185, P41GM103311, DE-AC02-06CH11357, AGM-12006, ACB-12002, T32GM007175, P30GM138396, R35GM122481, AGM-12006, P30GM138396)
- National Institute of Neurological Disorders and Stroke (R35NS097306)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, No. DE-AC02-06CH11357, 06CH11357, Contract No. DE-AC02-06CH11357., S10 OD012289)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- sigma-2 receptor, crystal structure, virtual screening, structure-based drug design, protein-ligand docking, neuropathic pain, mechanical hypersensitivity, spared nerve injury model, nociception
- MeSH terms
- Animals, Ligands, Neuralgia, Structure-Activity Relationship, Receptors, sigma, Mice
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