培氟沙星均三唑硫醚衍生物抗肝癌活性的CoMFA模型与分子设计

基于比较分子力场分析(CoMFA)方法建立24种培氟沙星均三唑硫醚衍生物抗肝癌活性(pM)的三维定量构效关系(3D-QSAR)。训练集中20个化合物用于建立预测模型,测试集10个化合物(含模板分子及新设计的5个分子)作为模型验证。已建立的3D-QSAR模型的交叉验证系数(R_cv²)、非交叉验证系数(R^₂)分别为0.705、0.940,说明所建模型具有较强的稳定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74.8%、25.2%,表明影响抗肝癌活性(pM)的主要因素是取代基的疏水性和空间契合,其次是库仑力、氢键及配位。基于三维等势图,设计了5个具有较高抗肝癌活性的分子,有待医学实验验证。

CoMFA Model and Molecular Design of Anti-liver Cancer Activity for Pefloxacin Isotriazole Sulfide Derivatives

Based on the comparative molecular field analysis(CoMFA) method, three dimensional quantitative structure-activity relationships (3D-QSAR) between the molecular structures and the in vitro anti-cancer activity (pM) of 24 pefloxacin isotriazole sulfide derivatives against human liver cancer cells (SMMC-7721) were established. Twenty compounds in the training set were served to build the predicting model, and the test set of ten compounds(containing template molecule and newly designed 5 molecules) were used to validate the model. The coefficient of the cross-validation (R_cv²) and non cross-validation (R²) for CoMFA model established in this study were 0.705 and 0.940, respectively. The results showed that the model has strong stability and good predictability. In this model, the contributions of the steric and electrostatic fields were 74.8% and 25.2%, respectively, indicating that the main factor to impact on pM was the hydrophobic factor and steric fit of substituted groups, followed by Coulomb force, hydrogen bonds and coordination of substituted groups. Base on the CoMFA contour maps, we also designed five novel molecules with satisfied prediction activity for the further experimental validation.