Binding site analysis of CCR2 through in silico methodologies: docking, CoMFA, and CoMSIA.

Chemokine receptor (CCR2) is a G protein-coupled receptor that contains seven transmembrane domains. CCR2 is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity and type 2 diabetes. Herein, we report on a binding site analysis of CCR2 through docking and three-dimensional quantitative structure-activity relationship (3D-QSAR). The docking study was performed with modeled receptor (CCR2) using β2-andrenergic receptor structure as a template. Comparative molecular field analysis (CoMFA)- and comparative molecular similarity indices analysis (CoMSIA)-based 3D-QSAR models were developed using two different schemes: ligand-based (CoMFA; q² =0.820, r² =0.966, r²(pred) = 0.854 and CoMSIA; q² =0.762, r² =0.846, r²(pred) = 0.684) and receptor-guided (CoMFA; q² =0.753, r² =0.962, r²(pred) =0.786, CoMSIA; q² =0.750, r² =0.800, r²(pred)=0.797) methods. 3D-QSAR analysis revealed the contribution of electrostatic and hydrogen bond donor parameters to the inhibitory activity. Contour maps suggested that bulky substitutions on the para position of R¹ substituted phenyl ring, electronegative and donor substitutions on meta (5') and ortho (2') position of R² substituted phenyl ring were favorable for activity. The results correlate well with previous results and newly report additional residues that may be crucial in CCR2 antagonism.