Cannabinoid CB2/CB1 selectivity. Receptor modeling and automated docking analysis.
Three-dimensional models of the CB1 and CB2 cannabinoid receptors were constructed by means of a molecular modeling procedure, using the X-ray structure of bovine rhodopsin as the initial template, and taking into account the available site-directed mutagenesis data. The cannabinoid system was studied by means of docking techniques. An analysis of the interaction of WIN55212-2 with both receptors showed that CB2/CB1 selectivity is mainly determined by the interaction in the CB2 with the nonconserved residues S3.31 and F5.46, whose importance was suggested by site-directed mutagenesis data. We also carried out an automated docking of several ligands into the CB2 model, using the AUTODOCK 3.0 program; the good correlation obtained between the estimated free energy binding and the experimental binding data confirmed our binding hypothesis and the reliability of the model.
Tuccinardi
Tiziano
T
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
Ferrarini
Pier Luigi
PL
Manera
Clementina
C
Ortore
Gabriella
G
Saccomanni
Giuseppe
G
Martinelli
Adriano
A
D000595:Amino Acid Sequence; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry; D048588:Benzoxazines; D002417:Cattle; D063388:Endocannabinoids; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009025:Morpholines / Q000737:chemistry; D009281:Naphthalenes / Q000737:chemistry; D009287:Naphthyridines / Q000737:chemistry; D053284:Polyunsaturated Alkamides; D011487:Protein Conformation; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry* / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000737:chemistry* / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D001095:Arachidonic Acids; D048588:Benzoxazines; D063388:Endocannabinoids; D007211:Indoles; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D009287:Naphthyridines; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D012243:Rhodopsin; C078814:anandamide