取代嘧啶衍生物抗前列腺癌活性的3D-QSAR研究

运用比较分子力场分析(CoMFA)方法,建立18种取代嘧啶衍生物抗前列腺癌活性(pM)的三维定量构效关系。训练集中15个化合物用于建立预测模型,测试集13个化合物(含10号模板分子和新设计的9个分子)作为模型验证。建立的CoMFA模型的交叉验证系数(R_ev²)、非交叉验证系数(R²)分别为0.344、0.935,说明所建模型具有较强的鲁棒性和良好的预测能力。该模型中立体场、静电场贡献率依次为71.6%、28.6%。影响取代嘧啶衍生物抗前列腺癌活性的主要因素是取代基的疏水作用和空间位阻,其次是取代基的库仑力、氢键及配位作用。基于此研究结果,设计了9个新化合物,其抗前列腺癌活性有待医学实验验证。

QSAR study on the anti-prostate cancer activity of substituted pyrimidine derivatives

To study the anti-prostate cancer mechanism of substituted pyrimidine derivatives. Based on the comparative molecular field analysis(CoMFA) method, three dimensional quantitative structure-activity relationships(3D-QSAR) between the molecular structures and their anti-nasopharyngeal squamous cancer activity (pM) of 18 substituted pyrimidine derivatives were established. Fifteen compounds in the training set were served to build the predicting model, and the thirteen compounds (containing template molecule 10 and designed nine novel molecules) in the test set were used to validate the model. The coefficients of the cross-validation (Rcv2) and non cross-validation (R2) for CoMFA model established in this study are 0.344 and 0.935, respectively. The results show that the model has strong stability and good predictability. In this model, the contributions of the steric and electrostatic fields were 71.4% and 28.6%, respectively. The main factors affecting the anti-prostate cancer activity (pM) of substituted pyrimidine derivatives are hydrophobic effect and steric hindrance of substituents, followed by coulomb force, hydrogen bond and coordination of substituents. Based on the results of this study, nine new compounds were designed, and their anti-prostate cancer activities need to be verified by medical experiments.