六种酪氨酸激酶抑制剂的电子结构与药效关系的理论研究

Theoretical study on the relationship between electronic structures and pharmaceutical effect of six tyrosine kinase inhibitors

苯胺喹唑啉类药物是一类典型的小分子表皮生长因子受体酪氨酸激酶抑制剂(EGFRTKIs)。该类化合物是ATP竞争性抑制剂,能抑制蛋白酪氨酸激酶磷酸化,从而阻断肿瘤细胞瀑布式的信号传递,是用于治疗非小细胞肺癌的常用药物。基于量子化学中的密度泛函理论(DFT),采用自洽反应场(SCRF)方法中的极化连续介质模型(Polarized Continuum Model,PCM)模拟水环境,在B3LYP/6-31+G(d)的水平下优化搜索得到了六种苯胺喹唑啉类EGFRTKIs的最稳定几何构型,并在CAM-B3LYP/6-311++G(d,p)水平下对其电子结构性质进行了系统的研究。基于理论计算可以推测此类药物靶点是EGFR受体上的富电子区域,所以分子的最低非占据轨道(LUMO)对于药物与靶点的结合起着关键作用。此外,概念密度泛函分析表明该类药物的垂直电离能、电负性及软硬度参数可能与其药效相关。上述研究结果为进一步改进此类药物的抗肿瘤性能以及设计、合成新型EGFR-TKIs药物分子提供了理论指导与依据。

The investigation on 4-anilinoquinazoline drugs,which are mostly used in the treatment of non-small cell lung cancer,has been a hot topic of the study on micromolecular EGFR-TKIs.These compounds are competitive inhibitors of ATP,inhibiting the phosphorylation of protein tyrosine kinase,and then block the waterfall signaling of tumor cells.Based on the density functional theory(DFT)in the quantum chemistry,the lowest-energy geometric structures of six tyrosine kinase inhibitors(EGFR-TKIs)were obtained at the B3 LYP/6-31+G(d)level.Herein,the polarized continuum model(PCM)in the self-consistent reaction field(SCRF)method was used to simulate the water environment.Based on the global minima,their electronic structure properties were calculated at the CAM-B3LYP/6-311++G(d,p)level.Based on the computations,it can be speculated that the target for these drugs are electron-rich region of EGFR,and thus the LUMOs of them play an important role in combining with the drug target.In addition,the concept density functional theoretical study shows that the VIE,electronegativity,softness,and hardness may be also relevant to pharmacodynamic properties of these drugs.This study may provide some theoretical guidance for the further improvement of the antitumor properties of these drugs as well as the design and synthesis of new EGFR-TKIs drugs.