Discovery of High-Affinity Cannabinoid Receptors Ligands through a 3D-QSAR Ushered by Scaffold-Hopping Analysis †

Two 3D quantitative structure–activity relationships (3D-QSAR) models for predicting Cannabinoid receptor 1 and 2 (CB(1) and CB(2)) ligands have been produced by way of creating a practical tool for the drug-design and optimization of CB(1) and CB(2) ligands. A set of 312 molecules have been used to build the model for the CB(1) receptor, and a set of 187 molecules for the CB(2) receptor. All of the molecules were recovered from the literature among those possessing measured K(i) values, and Forge was used as software. The present model shows high and robust predictive potential, confirmed by the quality of the statistical analysis, and an adequate descriptive capability. A visual understanding of the hydrophobic, electrostatic, and shaping features highlighting the principal interactions for the CB(1) and CB(2) ligands was achieved with the construction of 3D maps. The predictive capabilities of the model were then used for a scaffold-hopping study of two selected compounds, with the generation of a library of new compounds with high affinity for the two receptors. Herein, we report two new 3D-QSAR models that comprehend a large number of chemically different CB(1) and CB(2) ligands and well account for the individual ligand affinities. These features will facilitate the recognition of new potent and selective molecules for CB(1) and CB(2) receptors.