Download MendeleyVirtual library docking for cannabinoid-1 receptor agonists with reduced side effects.
Tummino, T.A., Iliopoulos-Tsoutsouvas, C., Braz, J.M., O'Brien, E.S., Stein, R.M., Craik, V., Tran, N.K., Ganapathy, S., Liu, F., Shiimura, Y., Tong, F., Ho, T.C., Radchenko, D.S., Moroz, Y.S., Rosado, S.R., Bhardwaj, K., Benitez, J., Liu, Y., Kandasamy, H., Normand, C., Semache, M., Sabbagh, L., Glenn, I., Irwin, J.J., Kumar, K.K., Makriyannis, A., Basbaum, A.I., Shoichet, B.K.(2025) Nat Commun 16: 2237-2237
- PubMed: 40044644
- DOI: https://doi.org/10.1038/s41467-025-57136-7
- Primary Citation of Related Structures:
9DGI, 9EGO - PubMed 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??M) 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.
Organizational Affiliation:
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
