Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects
Tia A. Tummino, Christos Iliopoulos‐Tsoutsouvas, João 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
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 (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.