The cannabinoid (CB) receptors, CB1 and CB2, which belong to the membrane-bound rhodopsin-like GPCR family, are implicated in the pathophysiology of various diseases. CB1 agonists have been well-studied as potential drugs for the attenuation of chemotherapy induced-vomiting, treatment of pain, and the management of multiple sclerosis and glaucoma, along with many other indications. A proper understanding of the dynamics of the CB1 receptor and an in-depth knowledge of the binding modes of CB1 agonists may assist in the discovery of new potential therapeutics targeting CB1 receptors. Active-state CB1 homology models were built using active-state X-ray structures of the adrenergic receptor β<sub>2</sub>-AR–Gs complex (PDB-ID: 3SN6) and bovine rhodopsin (PDB-ID: 3PQR) as the templates. A reported disulfide bridge between the second extracellular loop residues C257 and C264 was included. 100 CB1 models were generated and subjected to preliminary quality assessments including Discrete Optimized Protein Energy (DOPE) scores, GA341 scores, and Ramachandran plot analyses. A total of 66 models passed the above assessments and were further tested by docking of well-known mixed CB1/CB2 agonists. The best model was used for further studies. We performed a comprehensive structural analysis of features characteristic of active-state Class-A GPCRs including salt bridges, the CWxP motif, and the rotameric toggle switch. A comparison was also made with the poses of agonists docked into the inactive-state and active-state CB1 X-ray crystal structures and into our best active-state model, to compare and contrast interaction patterns. The salt bridge interaction between Lys192 and Asp176 found in the 5U09 and 5TGZ inactive-state crystal structures as well as in the 5XRA active-state crystal structure, made Lys192 unavailable for interaction with a CB1 ligand. However, in our active-state model, this ionic lock was absent, leaving Lys192 available for ligand binding; this corresponds to literature mutagenesis data supporting the importance of ligand interactions of Lys192. This study suggest that our active-state model could be useful to guide the design and synthesis of novel high affinity and selective agonists of the CB1 receptor

Active-state cannabinoid 1 (CB1) receptor: Protein modeling and comparison to recently published X-ray structures of the inactive-state and active-state CB1 receptors

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.