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 CB₁ 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 CB₁ antagonists. Figure Compounds 1-78 are aligned into the putative CB1 receptor binding site. The three key features shared by all of them are reported in coloured spheres. The hydrophobic/aromatic ones are depicted in purple while the acceptor functions are coloured in blue.