Binding Site Analysis of CCR2 Through In Silico Methodologies: Docking, CoMFA, and CoMSIA

作者：Kothandan Gugan; Gadhe Changdev G; Madhavan Thirumurthy; Cho Seung J^*

来源：Chemical Biology & Drug Design, 2011, 78(1): 161-174.

DOI：10.1111/j.1747-0285.2011.01095.x

• CCR2
• comparative molecular field analysis
• comparative molecular similarity indices analysis
• Genetic Algorithm Similarity Program
• pharmacophore
• 3D-QSAR

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 beta 2-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; q(2) = 0.820, r(2) = 0.966, r(pred)(2) = 0.854 and CoMSIA; q(2) = 0.762, r(2) = 0.846, r(pred)(2) = 0.684) and receptor-guided (CoMFA; q(2) = 0.753, r(2) = 0.962, r(pred)(2) = 0.786, CoMSIA; q(2) = 0.750, r(2) = 0.800, r(pred)(2) = 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 R(1) substituted phenyl ring, electronegative and donor substitutions on meta (5') and ortho (2') position of R(2) 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.

• 出版日期2011-7