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