Ligand-ligand and ligand-receptor approaches to modeling the cannabinoid CB1 and CB2 receptors: Achievements and challenges

The cannabinoid CB1 and CB2 receptors belong to the super family of G prote in-coupled receptors. Antagonists for each receptor subtype, as well as fou r structural classes of agonists that bind to both receptors, have been ide ntified. In the absence of an experimentally determined structure for each of these two receptors, computational molecular modeling approaches have be en employed to begin to probe structure-function relationships. Molecular m odeling studies have been approached from two perspectives: calculations in volving only ligands (Ligand-Ligand Approach) or calculations of the intera ction of a ligand with its receptor macromolecule (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 s ite from a correlation between experimentally determined biological activit ies and the structural and electronic features of a series of small molecul es. Ligand-Ligand Approaches result in development of pharmacophore models. Although closer to the event of interest, the study of the binding of a li gand to its receptor is less common because it requires a working knowledge of the receptor structure [54]. Mutation/chimera studies, as well as struc ture activity relationships can be used to test models developed in a Ligan d-Receptor Approach. This review considers both Ligand-Ligand and Ligand-Re ceptor computational studies of the CB1 and CB2 receptors. Challenges for f urther modeling studies are also identified.