2. Academic Validation
  3. Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects

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

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. kaavyak@stanford.edu.
  • 13 Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA. a.makriyannis@northeastern.edu.
  • 14 Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA. a.makriyannis@northeastern.edu.
  • 15 Department of Anatomy, University of California, San Francisco, San Francisco, CA, 94158, USA. allan.basbaum@ucsf.edu.
  • 16 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA. bshoichet@gmail.com.
  • # Contributed equally.
PMID: 40044644 DOI: 10.1038/s41467-025-57136-7
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 (Ki = 0.7 µM) leads to '1350, a 0.95 nM ligand and a full CB1R agonist of Gi/o signaling. A cryo-EM structure of '1350 in complex with CB1R-Gi1 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.

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