TY - JOUR
T1 - Homology modeling in tandem with 3D-QSAR analyses
T2 - A computational approach to depict the agonist binding site of the human CB2 receptor
AU - Cichero, Elena
AU - Ligresti, Alessia
AU - Allar, Marco
AU - Di Marzo, Vincenzo
AU - Lazzati, Zelda
AU - D'Ursi, Pasqualina
AU - Marabotti, Anna
AU - Milanesi, Luciano
AU - Spallarossa, Andrea
AU - Ranise, Angelo
AU - Fossa, Paola
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
KW - 3D-QSAR
KW - Cannabinoid receptor
KW - CB2 agonist
KW - CoMSIA
KW - Homology modeling
KW - MD simulations
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U2 - 10.1016/j.ejmech.2011.07.023
DO - 10.1016/j.ejmech.2011.07.023
M3 - Article
C2 - 21835510
AN - SCOPUS:80052930474
VL - 46
SP - 4489
EP - 4505
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
IS - 9
ER -