Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40044644.
- Also identified by DOI 10.1038/s41467-025-57136-7 and PMC identifier 11882969.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>i</sub> = 0.7 µM) leads to '1350, a 0.95 nM ligand and a full CB1R agonist of G<sub>i/o</sub> signaling. A cryo-EM structure of '1350 in complex with CB1R-G<sub>i1</sub> 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.
Medical subject headings
- Receptor, Cannabinoid, CB1
- Cannabinoid Receptor Agonists
- Cannabinoids
- Analgesics