Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar (Mohali), Punjab, 160 062, India.
J Biomol Struct Dyn. 2013;31(7):694-715. doi: 10.1080/07391102.2012.707460. Epub 2012 Aug 22.
CC chemokine receptor type-2 (CCR2) is a member of G-protein coupled receptors superfamily, expressed on the cell surface of monocytes and macrophages. It binds to the monocyte chemoattractant protein-1, a CC chemokine, produced at the sites of inflammation and infection. A homology model of human CCR2 receptor based on the recently available C-X-C chemokine recepor-4 crystal structure has been reported. Ligand information was used as an essential element in the homology modeling process. Six known CCR2 antagonists were docked into the model using simple and induced fit docking procedure. Docked complexes were then subjected to visual inspection to check their suitability to explain the experimental data obtained from site directed mutagenesis and structure-activity relationship studies. The homology model was refined, validated, and assessed for its performance in docking-based virtual screening on a set of CCR2 antagonists and decoys. The docked complexes of CCR2 with the known antagonists, TAK779, a dual CCR2/CCR5 antagonist, and Teijin-comp1, a CCR2 specific antagonist were subjected to molecular dynamics (MD) simulations, which further validated the binding modes of these antagonists. B-factor analysis of 20 ns MD simulations demonstrated that Cys190 is helpful in providing structural rigidity to the extracellular loop (EL2). Residues important for CCR2 antagonism were recognized using free energy decomposition studies. The acidic residue Glu291 from TM7, a conserved residue in chemokine receptors, is favorable for the binding of Teijin-comp1 with CCR2 by ΔG of -11.4 kcal/mol. Its contribution arises more from the side chains than the backbone atoms. In addition, Tyr193 from EL2 contributes -0.9 kcal/mol towards the binding of the CCR2 specific antagonist with the receptor. Here, the homology modeling and subsequent molecular modeling studies proved successful in probing the structure of human CCR2 chemokine receptor for the structure-based virtual screening and predicting the binding modes of CCR2 antagonists.
CC 趋化因子受体 2（CCR2）是 G 蛋白偶联受体超家族的成员，表达于单核细胞和巨噬细胞的细胞表面。它与单核细胞趋化蛋白-1（MCP-1）结合，MCP-1 是一种在炎症和感染部位产生的 CC 趋化因子。据报道，已经基于最近可用的 C-X-C 趋化因子受体-4 晶体结构构建了人 CCR2 受体的同源模型。配体信息被用作同源建模过程中的基本要素。使用简单和诱导拟合对接程序将六种已知的 CCR2 拮抗剂对接入模型中。对接复合物随后进行目视检查，以检查其是否适合解释通过定点诱变和结构-活性关系研究获得的实验数据。对同源模型进行了优化、验证，并对其在一组 CCR2 拮抗剂和诱饵的基于对接的虚拟筛选中的性能进行了评估。将已知拮抗剂 TAK779（一种双重 CCR2/CCR5 拮抗剂）和 Teijin-comp1（一种 CCR2 特异性拮抗剂）与 CCR2 的对接复合物进行分子动力学（MD）模拟，进一步验证了这些拮抗剂的结合模式。对 20ns MD 模拟的 B 因子分析表明，Cys190 有助于提供细胞外环（EL2）的结构刚性。使用自由能分解研究识别对 CCR2 拮抗作用重要的残基。TM7 中的酸性残基 Glu291（趋化因子受体中的保守残基）有利于 Teijin-comp1 与 CCR2 的结合，其结合自由能为-11.4kcal/mol。它的贡献更多地来自侧链而不是主链原子。此外，EL2 中的 Tyr193 对 CCR2 特异性拮抗剂与受体的结合贡献了-0.9kcal/mol。在这里，同源建模和随后的分子建模研究成功地探测了人 CCR2 趋化因子受体的结构，用于基于结构的虚拟筛选，并预测了 CCR2 拮抗剂的结合模式。
