Ligand-Ligand and Ligand-Receptor Approaches to Modeling the Cannabinoid CB1 and CB2 Receptors: Achievements and Challenges

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The cannabinoid CB1 and CB2 receptors belong to the super family of G protein-coupled receptors. Antagonists for each receptor subtype, as well as four structural classes of agonists that bind to both receptors, have been identified. In the absence of an exptl. detd. structure for each of these two receptors, computational mol. modeling approaches have been employed to begin to probe structure-function relationships. Mol. modeling studies have been approached from two perspectives: calcns. involving only ligands (Ligand-Ligand Approach) or calcns. of the interaction of a ligand with its receptor macromol. (Ligand-Receptor Approach) [49]. The Ligand-Ligand Approach does not directly consider the structure of the ligand binding site, but attempts to infer information about this site from a correlation between exptl. detd. biol. activities and the structural and electronic features of a series of small mols. Ligand-Ligand Approaches result in development of pharmacophore models. Although closer to the event of interest, the study of the binding of a ligand to its receptor is less common because it requires a working knowledge of the receptor structure [54]. Mutation/chimera studies, as well as structure activity relationships can be used to test models developed in a Ligand-Receptor Approach. This review considers both Ligand-Ligand and Ligand-Receptor computational studies of the CB1 and CB2 receptors. Challenges for further modeling studies are also identified.

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