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

Tia A Tummino; Christos Iliopoulos-Tsoutsouvas; Joao M Braz; Evan S O'Brien; Reed M Stein; Veronica Craik; Ngan K Tran; Suthakar Ganapathy; Fangyu Liu; Yuki Shiimura; Fei Tong; Thanh C Ho; Dmytro S Radchenko; Yurii S Moroz; Sian Rodriguez Rosado; Karnika Bhardwaj; Jorge Benitez; Yongfeng Liu; Herthana Kandasamy; Claire Normand; Meriem Semache; Laurent Sabbagh; Isabella Glenn; John J Irwin; Kaavya Krishna Kumar; Alexandros Makriyannis; Allan I Basbaum; Brian K Shoichet

doi:10.1038/s41467-025-57136-7

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.

Authors

Tia A Tummino^#^{1

2}, Christos Iliopoulos-Tsoutsouvas^#³, Joao M Braz^#⁴, Evan S O'Brien⁵, Reed M Stein^{1

2}, Veronica Craik⁴, Ngan K Tran³, Suthakar Ganapathy³, Fangyu Liu¹, Yuki Shiimura^{5

6}, Fei Tong³, Thanh C Ho³, Dmytro S Radchenko⁷, Yurii S Moroz^{7

8

9}, Sian Rodriguez Rosado⁴, Karnika Bhardwaj⁴, Jorge Benitez⁴, Yongfeng Liu¹⁰, Herthana Kandasamy¹¹, Claire Normand¹¹, Meriem Semache¹¹, Laurent Sabbagh¹¹, Isabella Glenn¹, John J Irwin¹, Kaavya Krishna Kumar¹², Alexandros Makriyannis^{13

14}, Allan I Basbaum¹⁵, Brian K Shoichet¹⁶

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.

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.

MeSH terms

Analgesics* / chemistry
Analgesics* / pharmacology
Animals
Cannabinoid Receptor Agonists* / adverse effects
Cannabinoid Receptor Agonists* / chemistry
Cannabinoid Receptor Agonists* / pharmacology
Cannabinoids* / chemistry
Cannabinoids* / pharmacology
Cryoelectron Microscopy
Humans
Ligands
Male
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
Receptor, Cannabinoid, CB1* / agonists
Receptor, Cannabinoid, CB1* / chemistry
Receptor, Cannabinoid, CB1* / metabolism

Substances

Receptor, Cannabinoid, CB1
Cannabinoid Receptor Agonists
Cannabinoids
Analgesics
Ligands

Abstract

MeSH terms

Substances

Grants and funding