胆红素代谢酶UGT1A1诱导剂高效筛选体系的构建与应用

胆红素代谢酶UGT1A1已经成为治疗高胆红素血症的新靶标。长期以来，由于缺乏面向复杂体系的胆红素代谢酶诱导剂有效性和安全性的同步精准高效评价体系，极大限制了强效安全的胆红素代谢酶诱导剂的开发。本项目拟在前期工作基础上，以团队自主研发的胆红素代谢酶光学探针底物为核心，结合高内涵成像仪在多参数同步评价中的优势，构建面向中药复杂成分的活细胞水平胆红素代谢酶诱导剂有效性与安全性的同步高效筛选方法。在此基础上，开展大量中药组分/单体对胆红素代谢酶诱导活性的高效筛选与精细评价。同时，联合分子动力学模拟，比较诱导剂结构细微改变对与诱导效应和诱导机制的影响。在定性和定量评价基础上，从中药资源中发现高效的天然胆红素代谢酶诱导剂，深入揭示胆红素代谢酶偏好的诱导剂结构规律。最终不仅可为理性发现胆红素代谢酶诱导以及先导化合物的合理改造提供研究基础，而且有望为国内外药物研发企业和单位提供高效的新药研发的关键技术。

UGT1A1 has been recognized as a new target for the treatment of hyperbilirubinemia. The lack of accurate and efficient evaluation system for the effectiveness and safety of bilirubin metabolizing enzyme inducers in complex biological systems greatly hindered the development of effective and safe bilirubin metabolizing enzyme inducers. The present project will use the bilirubin metabolizing enzyme optical probe developed by our previous work, and combine the advantages of high content imaging system, construct a system for the screening of effective and safe bilirubin metabolizing enzyme inducer in living cell system. Then, a large number of structural diversity of components from chinese traditional medicine was carried out to evaluate the inducible activity of bilirubin metabolizing enzyme. With the help of molecular simulation and experimental methods, the structure-activity relationship and induction mechanism of these inducers will be deeply discussed. Based on the qualitative and quantitative study, not only high efficient natural inducers of bilirubin metabolizing enzyme will be found but also the prefer structure of UGT1A1 inducer will be recovered. The study will provide theoretical basis and foundation rational modification of leading compound. Moreover, this may provide the key technology of efficient new drug research and development for domestic and foreign drug research and development enterprises and institute.