Modelling the cannabinoid receptor 2 in the agonist- and antagonist-bound conformations

SPINOSA, M.; CAVASOTTO, CLAUDIO N.

Santos (SP)

Congreso; XLII Congress of the Brazilian Biophysics Society (SBBf); 2017

There is growing interest in using cannabinoidreceptor 2 (CB2) agonists for the treatment of neuropathic pain, immune system,cancer, drug abuse, and other indications. The lack of a three-dimensionalstructure of this class A G protein-coupled receptor (GPCR) has hampered thedevelopment of structure-based drug discovery strategies, and the understandingof the differences at the conformational level between the inactive and activestates of the receptor. Moreover, only ~5% of all GPCRs (a super-family with>800 members) has been crystallized, what makes GPCR homology modelling achallenging task. Continuing with our earlier work, we developed enhancedstructural models of the agonist- and antagonist-bound CB2 receptor using theligand-steered homology modelling approach, different structural templates, andalso comparing with models developed using the very recent CB1 x-ray structures.These models were validated using small-scale virtual screening, making thenreadily usable for prospective drug lead discovery campaigns.