title: Homology modeling in tandem with 3D-QSAR analyses: a computational approach to depict the agonist binding site of the human CB2 receptor.
abstract: CB2 receptor belongs to the large family of G-protein coupled receptors (GPCRs) controlling a wide variety of signal transduction. The recent crystallographic determination of human β2 adrenoreceptor and its high sequence similarity with human CB2 receptor (hCB2) prompted us to compute a theoretical model of hCB2 based also on β2 adrenoreceptor coordinates. This model has been employed to perform docking and molecular dynamic simulations on WIN-55,212-2 (CB2 agonist commonly used in binding experiments), in order to identify the putative CB2 receptor agonist binding site, followed by molecular docking studies on a series of indol-3-yl-tetramethylcyclopropyl ketone derivatives, a novel class of potent CB2 agonists. Successively, docking-based Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) studies were also performed. The CoMSIA model resulted to be the more predictive, showing r(ncv)(2) = 0.96, r(cv)(2) = 0.713, SEE = 0.193, F = 125.223, and r(2)(pred) = 0.78. The obtained 3D-QSAR models allowed us to derive more complete guidelines for the design of new analogues with improved potency so as to synthesize new indoles showing high CB2 affinity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV n 3, 16132 Genova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.forename: Vincenzo
authors.initials: V
authors.lastname: di Marzo
authors.forename: Zelda
authors.initials: Z
authors.lastname: Lazzati
authors.forename: Pasqualina
authors.initials: P
authors.lastname: D'Ursi
authors.forename: Anna
authors.initials: A
authors.lastname: Marabotti
authors.forename: Luciano
authors.initials: L
authors.lastname: Milanesi
authors.forename: Andrea
authors.initials: A
authors.lastname: Spallarossa
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D021281:Quantitative Structure-Activity Relationship; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D043885:Receptor, Cannabinoid, CB2