<i>In silico</i>mapping of allosteric ligand binding sites in type‐1 cannabinoid receptor

Abstract

The recent resolution of the crystal structure of type-1 cannabinoid receptor (CB₁ ) and the discovery of novel modulators for this target open the way to the possibility of elucidating the structural requirements for CB₁ binding, and thereby facilitate a rational drug design. Compounds that target the orthosteric site of CB₁ in some cases have shown side effects. Allosteric modulators could potentially avoid these side effects by influencing binding and/or efficacy of orthosteric ligands. Here, we summarize and compare previous data on different putative allosteric binding sites observed in CB₁ homology models with an in silico docking study of the recently published crystal structure of the same receptor on endogenous and natural hydrophobic ligands that act as positive allosteric modulators and negative allosteric modulators of CB₁ . In particular, a lipid-exposed pocket targeted by most of the tested molecules is reported and discussed.