Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects
Virtual library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking agonists for the cannabinoid-1 receptor (CB1R), we dock 74 million tangible molecules and prioritize 46 high ranking ones for de novo synthesis and testing. Nine are active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (K<sub>i</sub> = 0.7 µM) leads to '1350, a 0.95 nM ligand and a full CB1R agonist of G<sub>i/o</sub> signaling. A cryo-EM structure of '1350 in complex with CB1R-G<sub>i1</sub> confirms its predicted docked pose. The lead agonist is strongly analgesic in male mice, with a 2-20-fold therapeutic window over hypolocomotion, sedation, and catalepsy and no observable conditioned place preference. These findings suggest that unique cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from analgesia, supporting the further development of cannabinoids as pain therapeutics.
Authors
- Alexandros Makriyannis (ORCID: https://orcid.org/0000-0003-3272-3687)
- Veronica Craik (ORCID: https://orcid.org/0000-0001-5463-1199)
- Laurent Sabbagh (ORCID: https://orcid.org/0000-0002-5097-4298)
- Yuki Shiimura (ORCID: https://orcid.org/0000-0002-9752-7399)
- Tia A. Tummino (ORCID: https://orcid.org/0000-0001-9155-820X)
- Yurii S. Moroz (ORCID: https://orcid.org/0000-0001-6073-002X)
- Allan I. Basbaum (ORCID: https://orcid.org/0000-0002-1710-6333)
- Brian K. Shoichet (ORCID: https://orcid.org/0000-0002-6098-7367)
- Herthana Kandasamy
- Kaavya Krishna Kumar (ORCID: https://orcid.org/0000-0003-2283-4033)
- Reed M. Stein
- Fei Tong (ORCID: https://orcid.org/0000-0003-2880-8135)
- Jorge Benitez
- Dmytro S. Radchenko (ORCID: https://orcid.org/0000-0001-5444-7754)
- John J. Irwin (ORCID: https://orcid.org/0000-0002-1195-6417)
- Isabella Glenn (ORCID: https://orcid.org/0009-0002-6443-1873)
- Ngan K. Tran (ORCID: https://orcid.org/0000-0002-6106-2833)
- Meriem Semache
- Evan S. O’Brien (ORCID: https://orcid.org/0000-0002-2260-7722)
- Claire Normand
- Karnika Bhardwaj (ORCID: https://orcid.org/0009-0000-1769-0210)
- Thanh C. Ho (ORCID: https://orcid.org/0000-0001-6880-7570)
- Sian Rodriguez Rosado
- Yongfeng Liu (ORCID: https://orcid.org/0000-0002-8649-7892)
- Fangyu Liu (ORCID: https://orcid.org/0000-0001-5022-0106)
- Joao Bráz (ORCID: https://orcid.org/0000-0002-5792-1017)
- Christos Iliopoulos‐Tsoutsouvas
- Suthakar Ganapathy (ORCID: https://orcid.org/0000-0003-3828-5382)
Institutions
- Kurume University (JP)
- University of North Carolina at Chapel Hill (US)
- Northeastern University (US)
- University of California, San Francisco (US)
- Taras Shevchenko National University of Kyiv (UA)
- Stanford Medicine (US)
- National Institute of Mental Health (US)
- Enamine (Ukraine) (UA)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1038/s41467-025-57136-7
- Citations
- 10
- Primary Topic
- Pharmacological Receptor Mechanisms and Effects
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- Open Philanthropy Project
- National Institutes of Health
- Defense Advanced Research Projects Agency
- National Institute of Mental Health