趋化因子受体CXCR4抑制剂的三维定量构效关系及与其受体间的分子对接研究

Study on 3D-QSAR of CXCR4 Receptor Inhibitor and Its Molecular Docking with Their Receptors

目的:为设计新型趋化因子受体CXCR4抑制剂提供参考。方法:从文献中收集38个CXCR4受体抑制剂的结构与活性数据[半数抑制浓度(IC_(50))],使用Sybyl-X 2.0软件,运用第二代比较分子场法(即Topomer CoMFA),构建CXCR4受体抑制剂的三维定量构效关系(3D-QSAR)模型,使用18个样本的测试集验证模型的外部预测能力,并针对CXCR4受体抑制剂与CXCR4受体的立体场与静电场进行分析各R基团的取代基与活性的关系;使用Sybyl-X 2.0软件进行分子对接,分析CXCR4受体抑制剂与CXCR4受体之间的相互关键作用。结果:所得Topomer CoMFA模型的交叉验证系数Q^2=0.735,拟合验证系数R^2=0.959,Fisher验证值F=416.4,经过分子切割后和三维等势图分析,在R1基团的末端的取代基加入大体积且正电性强的基团有利于活性的提高;在R2基团附近引入体积较大且负电性较强的取代基有利于活性的提高;R3基团附近引入体积小及正电性强的取代基有利于活性的提高。分子对接结果显示,CXCR4受体抑制剂与Asp97、Glu288和Trp94等关键氨基酸残基有相互作用。结论:构建的Topomer CoMFA模型具有良好的预测能力和统计学稳定性,CXCR4受体抑制剂与受体靶标蛋白之间具有较强的氢键作用。3D-QSAR和分子对接研究结果可为CXCR4受体抑制剂分子的设计、改造及药物研发提供参考。

OBJECTIVE:To provide reference for designing new CXCR4 receptor inhibitor.METHODS:The data of structure and active value(IC50)of 38 CXCR4 receptor inhibitors were collected from the literatures.Using Sybyl-X 2.0 software,3D-QSAR model of CXCR4 receptor inhibitors was established with Topomer CoMFA.The external predictive power of the model was validated with test set for 18 samples.The relationship of R-group substituent group with activity was analyzed according to stereoscopic and electrostatic fields of inhibitors and CXCR4 receptors.Sybyl-X 2.0 software was used for molecular docking,and the key interaction between inhibitor and CXCR4 receptor were analyzed.RESULTS:The cross validation coefficients Q2 of Topomer CoMFA model was 0.735.The fitting validation coefficient R2 was 0.959,and Fisher validation value F was 416.4.After molecular splitting and three dimensional equipotential map analysis,the addition of big volume and positive charge group at the end of R1 group was beneficial to the improvement of the activity of CXCR4 receptor inhibitors.The introduction of substituent group with large volume and negative charge around R2 group was beneficial to the improvement of its activity.The introduction of substituent group with small volume and negative charge around R3 group was beneficial to the improvement of its activity.Molecule docking results showed the inhibitors interaction between CXCR4 receptor inhibitors and key amino acid residues as Asp97,Glu288 and Trp94.CONCLUSIONS:Established Topomer CoMFA model shows good predictability and statistical stability.CXCR4 receptor inhibitors have strong hydrogen bonding role with receptor target protein.3D-QSAR and molecular docking study can provide reference for the design,reconstruction and R&D of CXCR4 receptor inhibitor molecule.