Ligand-steered Modeling of the Cannabinoid Receptor 2: Successful Applications to Rationalize SAR Data of Selective CB2 Inverse Agonist and Agonist Compounds

PHATAK, SHARANGDHAR S; DIAZ, PHILIPPE; XU, J.; DIAZ, FANNY-ASTRUC; NAGUIB, MOHAMMED; CAVASOTTO, CLAUDIO N.

Galveston, TX

Simposio; 15th Annual Structural Biology Symposium; 2010

G-Protein Coupled Receptors (e.g. Cannabinoid Receptor 2) are the target of nearly 50% of drug discovery programs. CB2 is an emerging target for neuropathic pain and inflammation. Structure-based drug discovery (SBDD) for CB2 and other GPCRs is hampered by the limited availability of experimental GPCR structures. While homology modeling may provide crude models of the target, improving the accuracy, incorporating ligand / receptor flexibility and applicability of such models (even crystal structures) to SBDD remains  a matter of active research. Cavasotto et al. successfully developed the ligand-steered modeling of the binding site, to refine and incorporate receptor and ligand flexibility in the homology modeling process.  In a subsequent application, ligand-steered models of MCHR-1 receptor (an anti-obesity target) were developed and used in a structure-based drug discovery scenario, where low micromolar inhibitors with novel chemotypes were found. In this study, the ligand-steered method was adapted to develop models depicting two states (inactive and active) of the CB2 receptor. The models were successfully applied in a structure-based study to rationalize the structure-activity relationship data of potent and selective CB2 compounds.  Ligand-steered modeling offers an elegant way to model a wide variety of proteins and is suited for various structure-based drug discovery applications.