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, = 0.854 and CoMSIA; q² = 0.762, r² = 0.846, = 0.684) and receptor‐guided (CoMFA; q² = 0.753, r² = 0.962, = 0.786, CoMSIA; q² = 0.750, r² = 0.800, = 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.