Exploring the binding features of rimonabant analogues and acyclic CB1 antagonists: docking studies and QSAR analysis.
In order to elucidate the structural requirements for human CB(1) receptor antagonism, 78 antagonists belonging to five different chemical classes were selected from the literature and docked into the receptor binding site, built by homology modeling techniques. To further explore the structure-activity relationships within the considered chemical classes, a pharmacophore model and a QSAR analysis were developed. In a first step five alignments, one for each group of compounds were generated. All of them were then submitted to a MOE pharmacophore search in order to obtain a final pharmacophore model representative of the whole dataset which was used to elaborate the following 3D-QSAR analysis, by means of the CoMFA methodology. The results of these investigations are expected to be useful in the process of design and development of new potent CB(1) antagonists.
Cichero
Elena
E
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Genova, Italy.
Menozzi
Giulia
G
Spallarossa
Andrea
A
Mosti
Luisa
L
Fossa
Paola
P
D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077285:Rimonabant; D013329:Structure-Activity Relationship
D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant