苯并咪唑类化合物抗宫颈癌活性的3D-QSAR及分子对接研究

3D-QSAR and molecular docking study of the anti-cervical cancer activity of benzimidazole derivatives

目的研究苯并咪唑类衍生物抗宫颈癌的构效关系,对其进行合理设计与修饰,并运用分子对接技术模拟化合物与PI3Kα以及微管蛋白的作用方式。方法运用比较分子力场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)对30个苯并咪唑类衍生物进行三维定量构效关系(3D-QSAR)分析,同时采用分子对接研究化合物与PI3Kα亚型激酶4JPS、微管蛋白1SA0之间的相互作用方式。结果与结论构建的CoMFA(q^(2)=0.618,R^(2)=0.877)和CoMSIA(q^(2)=0.612,R^(2)=0.855)模型具有良好的统计学意义和预测能力,依据该模型设计9个新化合物,其中化合物33预测值最高。分子对接显示化合物33可与4JPS的Asn467、1SA0的Asp251氨基酸残基形成氢键作用,结合能高于模板化合物16。本研究可为苯并咪唑类PI3Kα和微管蛋白双重抗宫颈癌药物的设计和结构优化提供参考。

To investigate the structure-activity relationships of benzimidazole derivatives as anti-cervical cancer agents,a molecular docking study was carried out to simulate the mode of action of the compounds with PI3Kαand microtubule proteins.The 3D-QSAR analysis of thirty benzimidazole derivatives was completed through comparative molecular field analysis(CoMFA)and comparative molecular similarity index analysis(CoMSIA)methods.The constructed CoMFA(q^(2)=0.618,R^(2)=0.877)and CoMSIA(q^(2)=0.612,R^(2)=0.855)models had good statistical significance and predictive ability.Among the nine new compounds designed based on this model,compound 33 had the highest predicted value.Molecular docking showed that compound 33 could form hydrogen bonds with amino acid residues of Asn467 of 4JPS and Asp251 of 1SA0,and its binding energy was higher than that of the template compound 16.This study will provide theoretical reference for the design and structure optimization of benzimidazole-based dual PI3Kαand microtubule protein inhibitors against cervical cancer.