Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects
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.
Article Details
Authors (28)
Tia A. Tummino
Christos Iliopoulos-Tsoutsouvas
Joao M. Braz
Department Anatomy, University of California
Evan S. O’Brien
Reed M. Stein
Veronica Craik
Ngan K. Tran
Suthakar Ganapathy
Fangyu Liu
Yuki Shiimura
Fei Tong
Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
Thanh C. Ho
Dmytro S. Radchenko
Yurii S. Moroz
Sian Rodriguez Rosado
Karnika Bhardwaj
Jorge Benitez
Yongfeng Liu
State Key Laboratory of Silicon Materials and School of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, China
Herthana Kandasamy
Claire Normand
Meriem Semache
Laurent Sabbagh
Isabella Glenn
John J. Irwin
Kaavya Krishna Kumar
Alexandros Makriyannis
Allan I. Basbaum
Department Anatomy, University of California
Brian K. Shoichet