基于密度泛函的叶酸受体亚型介导的靶向荧光探针分子设计及其作用机制研究

Folate receptor (FR), which is higher expressed in human tumor cell membrane surface, can be used as a target for targeting delivery of anticancer drug. Tumor and inflammation, which express FR-α and FR-β respectively, can be targeted by folate conjugate simulataneously, which causes interference of diagnosis and chemotherapy for cancer. Therefore the research of novel folate derivative targeted with folate receptor subtype is significant. This subject will design a novel fluorescent probe targeted to FR subtype by studying the interactions between functional groups and FR subtype, and analyze the stable conformer and properties using density functional methods and molecular dynamics, and the fluorescent probe model will be built. The fluorescent probe/FR subtype model will be also built by docking novel fluorescent probe with FR-α and FR-β respectively. Further, the targeting effect of the novel fluorescent probe will be tested experimentally, the fluorescent probe model will be optimized, the molecular structure of fluorescent probe with high selectively with FR-α will be obtained, and the recognition accuracy of the tumor cell will be improved. This research is helpful for the design of targeted drug delivery system.

叶酸受体在肿瘤细胞膜表面高度表达，可作为靶点用于抗癌药的靶向投递，肿瘤和炎症区域分别表达叶酸受体亚型FR-α和FR-β，却同时被叶酸复合物识别，对癌症的诊断和治疗造成干扰。因此研究对叶酸受体亚型特异性结合的新型生物探针分子具有重要的应用意义。本课题拟通过分析形成分子间弱相互作用的功能团与叶酸受体亚型的作用，选择合适功能团设计对叶酸受体亚型具有良好选择性的新型荧光探针分子，采用分子动力学结合密度泛函的方法确定荧光探针分子的稳定构型及其理化参数，建立荧光探针分子结构模型。将荧光探针分子和叶酸受体亚型FR-α和FR-β进行分子对接，分析二者的作用机理，建立荧光探针/叶酸受体亚型结构模型。通过实验对荧光探针分子的特异靶向性进行验证和分析，进一步改善荧光探针分子模型，优化与FR-α特异性高的荧光探针靶向分子结构，有效提高肿瘤细胞靶向识别的准确性，为叶酸受体亚型介导的靶向药物传递研究提供策略。

由于叶酸受体在一些肿瘤组织中高水平表达，因此对叶酸进行改性设计新型的探针分子，改善叶酸受体亚型FRɑ和FRβ的靶向识别，具有重要的应用价值。本项目通过引入不同类型和尺寸的功能团（含电负性原子的-COOH、-OH、-NH2、-CH3、蝶啶、苯环等环装结构）设计了一系列的新型荧光探针分子（共59个结构），将探针分子与叶酸受体进行分子对接和分子动力学模拟,并进一步采用紧束缚的密度泛函的方法进行了计算。通过对复合物的结合能、分子轨道、氢键作用、均方根偏差,均方根涨落等性质的计算，详细地分析了二者的作用机制。通过分析复合物的结构和性质，找出了对FRɑ具有较好靶向选择性的新型荧光探针分子。本项目的结论为叶酸受体亚型介导的靶向探针分子设计提供依据。