Departments of Bio-New Drug Development, College of Medicine, Chosun University, Gwangju, South Korea.
Chem Biol Drug Des. 2011 Jul;78(1):161-74. doi: 10.1111/j.1747-0285.2011.01095.x. Epub 2011 Mar 29.
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.
趋化因子受体（CCR2）是一种 G 蛋白偶联受体，包含七个跨膜结构域。CCR2 是关节炎、多发性硬化症、血管疾病、肥胖症和 2 型糖尿病等疾病的靶点。在此，我们通过对接和三维定量构效关系（3D-QSAR）报告了 CCR2 的结合位点分析。对接研究使用β2-肾上腺素能受体结构作为模板对模型化受体（CCR2）进行。基于比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）的 3D-QSAR 模型使用两种不同的方案开发：配体为基础（CoMFA；q² = 0.820，r² = 0.966，r²（pred）= 0.854 和 CoMSIA；q² = 0.762，r² = 0.846，r²（pred）= 0.684）和受体为导向（CoMFA；q² = 0.753，r² = 0.962，r²（pred）= 0.786，CoMSIA；q² = 0.750，r² = 0.800，r²（pred）= 0.797）。3D-QSAR 分析表明，静电和氢键供体参数对抑制活性有贡献。等高线图表明，R¹取代的苯基环对位上的大取代基、R²取代的苯基环间位（5'）和邻位（2'）上的电负性和供体取代基有利于活性。结果与先前的结果相符，并新报告了可能对 CCR2 拮抗作用至关重要的额外残基。
