Large library docking for cannabinoid-1 receptor agonists with reduced side effects

Abstract

Docking tangible virtual libraries can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones forde novosynthesis and testing. Nine were active by radioligand competition, with > 50% radioligand displacement, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki= 731 nM) led to‘3234, a 1.9 nM binder and a full CB1 agonist. A cryo-EM structure of the‘3234-CB1-Gi1complex confirmed its docked pose, providing a template for further optimization. The new agonist was strongly analgesic especially against thermal pain, with a 10-fold therapeutic window over sedation and no observable catalepsy or conditioned place preference or aversion. These findings suggest that new cannabinoid chemotypes may be able to disentangle the characteristic “tetrad” side-effects from its desired analgesic effect, supporting the further development of cannabinoids as pain therapeutics.

Identifying Artifacts from Large Library Docking

“…Cannabinoid receptor type 1 (CB1) [24] GPCR 300,000 Dopamine receptor D 4 (D4) [6] GPCR 300,000 α2a adrenergic receptor (Alpha2a) [9] GPCR 165,000…”

“…Here again, we sought cases where docked ligands had been tested, admittedly in the 40-molecule range rather than the 500 to 1500 as with σ2, dopamine D4, and AmpC, but nevertheless revealing both true ligands and false positives. There are by now close to twenty of theses [1,4,6,8,9,[11][12][13][22][23][24][25][26], we focused on nine to which we had ready access (Table 1). Against each target hundreds of millions to billions of compounds had been docked; we rescored the several hundred-thousand top-ranking poses.…”

Characterization of binding kinetics and intracellular signaling of new psychoactive substances targeting cannabinoid receptor using transition-based reweighting method

“…[15][16][17] However, the pharmacological potential of these molecules was diminished due to their psychological and physiological side effects ("tetrad" side effect). [18][19][20] One such example of a synthetic cannabinoid is 1,1-Dimethylheptyl-11-hydroxy-tetrahydrocannabinol (commonly known as HU-210), which is a Schedule I controlled substance in the United States. 21,22 Apart from the canonical structures of synthetic cannabinoids, molecules with diverse scaffolds were also synthesized through structure-activity studies [23][24][25] .…”

“…15–17 However, the pharmacological potential of these molecules was diminished due to their psychological and physiological side effects (“tetrad” side effect). 18–20 One such example of a synthetic cannabinoid is 1,1-Dimethylheptyl-11-hydroxy-tetrahydrocannabinol (commonly known as HU-210), which is a Schedule I controlled substance in the United States. 21,22…”