香豆素类化合物抑制CYP1A亚型酶活性的构效关系及其机制研究

人细胞色素P4501A（CYP1A），包括CYP1A1和CYP1A2两个亚型，是介导异源物代谢激活诱发肿瘤的关键酶，抑制CYP1A的活性被认为是预防癌症的一种有效手段。但由于两亚型偏好抑制剂结构迥异，且CYP1A亚型特异性探针底物相对缺乏，极大的限制了CYP1A1和CYP1A2与抑制剂相互作用机制的研究。本项目以自主开发的CYP1A亚型特异性荧光探针为核心，以香豆素类作为模式化合物，构建结构多样的化合物库，系统评价其对CYP1A各亚型的抑制行为，结合计算模拟和定点突变技术，比较小分子结构和大分子关键氨基酸位点的差异对化合物与CYP1A相互作用的影响，深入揭示结构-CYP1A抑制活性关系，以及化合物对CYP1A1和CYP1A2活性抑制差异的关键影响因素与机制。以期为指导CYP1A亚型抑制剂的开发及先导化合物的结构优化提供理论依据，并为阐明CYP1A亚型对癌症发生的作用机制提供研究基础。

Human Cytochrome P450 1A (CYP1A), include CYP1A1 and CYP1A2, is responsible for the bioactivation of procarcinogens leading to certain types of cancers. Its inhibition has become an important target of cancer chemoprevention. As the structures of the preferred inhibitors of CYP1A isoforms are different, and the lack of isoform-specific probes for CYP1A greatly hindered the depth understanding of the structure differences and molecular mechanism of inhibitors between CYP1A1 and CYP1A2. This project will systematically investigate the inhibitory effects of coumarins against CYP1As by using self-developed isoform specific optical probe of CYP1As and constructing a compound library of coumarins from qualitative and quantitative aspects. In addition, molecular calculation simulation as well as amino acids mutation will be employed to study the interactions of CYP1A1 and CYP1A2 with ligands, which will uncover the key amino acid. Eventually, the structure inhibition relationships of coumarins against CYP1A isoforms and the mechanisms of different inhibition behaviors will be revealed from both small molecule and macromolecule approaches. Moreover, this project will not only provide guidance and foundation for the rationally development of CYP1A inhibitors and reasonable modification of coumarins, but also for the development of the mechanisms between CYP1A isoforms and related cancers.