Cited by 217Pharmacological Receptor Mechanisms and EffectsReceptor Mechanisms and SignalingComputational Drug Discovery Methods

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Structures of the σ2 receptor enable docking for bioactive ligand discovery

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Alon, Assaf, Lyu, Jiankun, Braz, Joao M., Tummino, Tia A., Craik, Veronica, O’Meara, Matthew J., Webb, Chase M., Radchenko, Dmytro S., Moroz, Yurii S., Huang, Xi-Ping, Liu, Yongfeng, Roth, Bryan L., Irwin, John J., Basbaum, Allan I., Shoichet, Brian K., Kruse, Andrew C.·2021·Nature

DOI 10.1038/s41586-021-04175-xPMC PMC8867396

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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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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: Alon, Assaf
Lyu, Jiankun
Braz, Joao M.
Tummino, Tia A.
Craik, Veronica
O’Meara, Matthew J.
Webb, Chase M.
Radchenko, Dmytro S.
Moroz, Yurii S.
Huang, Xi-Ping
Liu, Yongfeng
Roth, Bryan L.
Irwin, John J.
Basbaum, Allan I.
Shoichet, Brian K.
Kruse, Andrew C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2021-12-08
Volume: 600
Issue: 7890
Pages: 759-764
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-021-04175-x
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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