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 () and Brian K. Shoichet ()
Additional contact information
Tia A. Tummino: San Francisco
Christos Iliopoulos-Tsoutsouvas: Northeastern University
Joao M. Braz: San Francisco
Evan S. O’Brien: Stanford University School of Medicine
Reed M. Stein: San Francisco
Veronica Craik: San Francisco
Ngan K. Tran: Northeastern University
Suthakar Ganapathy: Northeastern University
Fangyu Liu: San Francisco
Yuki Shiimura: Stanford University School of Medicine
Fei Tong: Northeastern University
Thanh C. Ho: Northeastern University
Dmytro S. Radchenko: Enamine Ltd.
Yurii S. Moroz: Enamine Ltd.
Sian Rodriguez Rosado: San Francisco
Karnika Bhardwaj: San Francisco
Jorge Benitez: San Francisco
Yongfeng Liu: University of North Carolina at Chapel Hill School of Medicine
Herthana Kandasamy: Domain Therapeutics North America Inc.
Claire Normand: Domain Therapeutics North America Inc.
Meriem Semache: Domain Therapeutics North America Inc.
Laurent Sabbagh: Domain Therapeutics North America Inc.
Isabella Glenn: San Francisco
John J. Irwin: San Francisco
Kaavya Krishna Kumar: Stanford University School of Medicine
Alexandros Makriyannis: Northeastern University
Allan I. Basbaum: San Francisco
Brian K. Shoichet: San Francisco

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57136-7

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