Rimonabant (SR141716A), a selective blocker of the cannabinoid 1 (CB1) G-protein coupled receptor (GPCR), is an anti-obesity drug that causes serious side effects including depressionand increased risk of suicide. In order to develop receptor specific drugs to minimize such consequences, we aim to predict the CB1 receptor structure from first principles using a GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) method.  Thedocking results from a hierarchical docking program (DarwinDock) operating on the GEnSeMBLE output show that rimonabant is anchored by W5.43 and K3.28 in the CB1 protein, which is consistent with site-directed mutagenesis data.  The phenyl rings of rimonabant sandwich W5.43.  The ligand's carbonyl forms a hydrogen bond with K3.28, which is common in other analog docking to the CB1 receptor.  We expect this study will lead to more effective drug candidates for obesity diseases with reduced side effects.

Predicting the structure and the binding site of rimonabant for the cannabinoid CB1 receptor

240th National Meeting (2010)

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