炔基苯氧乙酸类CRTH2拮抗剂的3D-QSAR研究

3D-QSAR studies on Alkynyl phenoxy acetic acids as potent CRTH2 inhibitors

目的建立CRTH2拮抗剂的3D-QSAR模型。方法采用比较力场分析(CoMFA)法和比较分子相似性指数分析(CoMSIA)法对103个炔基苯氧乙酸类CRTH2拮抗剂进行三维定量构效关系(3D-QSAR)研究,建立了具有良好预测能力的模型。结果 CoMFA法所建模型的交互验证系数q2为0.763,线性回归系数r2为0.931,最佳主成分数是6。CoMSIA法采用立体场、静电场、疏水场、氢键供体场所建模型性能最佳,其中q2和r2分别为0.644、0.904;最佳主成分数是6。结论 3D-QSAR模型及力场贡献值分析揭示了分子结构和结合常数间的关系,为今后的炔基苯氧乙酸类化合物的设计改造提供了更直接可行的线索。

CRTH2 receptor plays an important role in the nosogenesis of inflammatory diseases. In this study, the 3D-QSAR of 103 alkynyl acetic acid antagonists was analyzed by CoMFA and CoMSIA methods to establish a good predictive model. The best 3D-QSAR model was obtained with cross-validated correlation coefficient q^2 values, the calibrated correlation coefficient （r^2） and principal-component （n） of 0.763, 0.931 and 6 for CoMFA, respectively. The best results of CoMSIA model was built by steric, electrostatic, hydrophobic, hydrogen bond aeceptor field. The q^2 values, r^ and n of CoMSIA are 0.644, 0.904 and 6. The result reveals the relationship between molecular structure and binding constant, and would benefits the future rational design of potent antagonists.