Ligand-based homology modelling of the human CB2 receptor SR144528 antagonist binding site: a computational approach to explore the 1,5-diaryl pyrazole scaffold

• Main Authors: Cichero, Elena, Menozzi, Giulia, Guariento, Sara, Fossa, Paola
• Format: Article
• Language: English
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c5md00333d

CB 1 and CB 2 receptors belong to the large family of G-protein coupled receptors (GPCRs), being involved in a wide variety of signal transduction processes. In this context, CB 2 selective compounds were described in the literature to be active in different neuropathic and inflammatory pain models, also showing beneficial effects as neuroprotective agents. Indeed, CB 2 proved to be up-regulated in reactive microglial cells in Alzheimer's disease (AD) and Huntington's, suggesting a promising therapeutic panorama for CB 2 inverse agonists/antagonists. At present, the development of new selective CB 2 antagonists is prevented by an unclear depiction of the reference antagonist SR144528 binding mode. Indeed, a few number of models concerning the CB 2 receptor antagonist binding site have been proposed, leading sometimes to contradictory results. In this context, a specific h CB 2 ligand-based homology model in the presence of the antagonist SR144528 was built. Notably, the refined model also allowed us to explore the pyrazole scaffold as prototype for CB 2 ligand recognition and also to elucidate the CB 1 /CB 2 structure-activity relationship of an in-house series of analogues we previously published. The derived information is expected to be a useful tool for guiding a much more focused and reliable CB 2 antagonist design. SR144528 docking mode into the LBHM of the human CB 2 receptor antagonist binding site.