Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects PMID: 40044644

ADC Targets in Oncology

2026-04-10

Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects

Nat Commun. 2025 Mar 6;16(1):2237. doi: 10.1038/s41467-025-57136-7.

Tia A Tummino ^# ¹ ² , Christos Iliopoulos-Tsoutsouvas ^# ³ , Joao M Braz ^# ⁴ , Evan S O'Brien ⁵ , Reed M Stein ¹ ² , Veronica Craik ⁴ , Ngan K Tran ³ , Suthakar Ganapathy ³ , Fangyu Liu ¹ , Yuki Shiimura ⁵ ⁶ , Fei Tong ³ , Thanh C Ho ³ , Dmytro S Radchenko ⁷ , Yurii S Moroz ⁷ ⁸ ⁹ , Sian Rodriguez Rosado ⁴ , Karnika Bhardwaj ⁴ , Jorge Benitez ⁴ , Yongfeng Liu ¹⁰ , Herthana Kandasamy ¹¹ , Claire Normand ¹¹ , Meriem Semache ¹¹ , Laurent Sabbagh ¹¹ , Isabella Glenn ¹ , John J Irwin ¹ , Kaavya Krishna Kumar ¹² , Alexandros Makriyannis ¹³ ¹⁴ , Allan I Basbaum ¹⁵ , Brian K Shoichet ¹⁶

Affiliations

1. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
2. Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, CA, 94158, USA.
3. Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA.
4. Department of Anatomy, University of California, San Francisco, San Francisco, CA, 94158, USA.
5. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
6. Division of Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka, Japan.
7. Enamine Ltd., 67 Winston Churchill Street, Kyiv, 02094, Ukraine.
8. National Taras Shevchenko University of Kyiv, 60 Volodymyrska Stree, Kyiv, 01601, Ukraine.
9. Chemspace LLC, 85 Winston Churchill Street, Suite 1, Kyiv, 02094, Ukraine.
10. National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA.
11. Domain Therapeutics North America Inc., Montréal, Québec, H4S 1Z9, Canada.
12. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA. [email protected].
13. Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA. [email protected].
14. Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA. [email protected].
15. Department of Anatomy, University of California, San Francisco, San Francisco, CA, 94158, USA. [email protected].
16. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA. [email protected].
# Contributed equally.

Abstract

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_i = 0.7 µM) leads to '1350, a 0.95 nM ligand and a full CB1R agonist of G_i/o signaling. A cryo-EM structure of '1350 in complex with CB1R-G_i1 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.