以配位化学关联手性结构特征探究中药熟地黄通过自噬-溶酶体途径治疗帕金森病的物质基础

Rehmannia glutinosa is effective for the treatment of Parkinson’s disease. The iridoid constituents of that contains multiple chiral centers, hydroxyl and carboxyl groups, which have been confirmed to be effective for PD by regulating autophagy-lysosome pathway. However, the study on the effective substances of Rehmanniaglutinosa is limited to the level of the common active ingredients, its multi-level structure characteristics (including skeleton, substituent and chirality) have not been explored, as well as the effect of the coordination form of metal ions and effective components. Besides, there is no systematic report about the effective substances of Rehmanniaglutinosa on the multiple target molecular networks in autophagy pathway. Our subject will carry out under the guidance of "integrity" and "coordination chemistry" of traditional Chinese Medicine. At the micro level, it is not only study the multi-level structure characteristics of free active ingredients of Rehmanniaglutinosa, but also explore the rules of active substances in the form of coordination, thus enriching the scientific connotation of coordination chemistry of TCM. At the macro level, with the assistance of CADD, variousmethods such as proteomics and bioinformatics, we can establish a drug-disease-target system to fully analyze the molecular mechanism of the PD’s treatment by using Rehmanniaglutinosa. This project can lay a solid foundation for the clinical application of Rehmanniaglutinosa, and develop innovative drugs.

熟地黄有补肾益精充髓之效，治疗帕金森病疗效确切，其环烯醚萜类活性成分结构中具多手性中心，并含有羟基、羧基等配位基团，该类成分已证实可通过调控自噬-溶酶体治疗PD。然而，目前对熟地黄的药效物质研究，仅局限于常规活性成分的层面，对其多层次结构特征（骨架/取代基/手性）未深入探索；还未考虑金属离子与药效成分的配位形态对药效的影响。此外，熟地黄活性成分在自噬途径上“多靶点”的分子网络还未见系统报道。本课题拟在中医药“整体性”、“配位化学”指导下，在微观层次上，既研究熟地黄游离活性成分的多层次结构特征，也探索药效物质在配合形态下的作用规律，充实“中药配位化学学说”的科学内涵；在宏观层次上，借助CADD、各种组学与生物信息学等手段，建立药物-疾病-靶点网络，更全面地解析熟地黄治疗PD的“多靶点”分子网络机制。本项目的开展，可对熟地黄在临床上的安全合理应用，开发熟地黄创新药物打下坚实的基础。

本项目制备了多样性的熟地黄环烯醚萜类成分与类药效物质库合集，借助生物信息学技术探索熟地黄活性成分及合成类似成分在诱导自噬通路上的成分-靶点关系，并利用现代分子生物学技术开展熟地黄环烯醚萜体内外药效学及分子作用机制。本项目从中药整体效应出发，探索熟地黄药效物质，并利用生物电子等排设计、生物电子多样性向导合成、骨架跃迁的思路，通过逆合成分析和化学合成、半合成手段，立体选择性制备结构片段、取代基、手性中心多样性，且与熟地黄活性成分骨架具有相关性的小型化合物库（群）；同时，课题组研究了熟地黄环烯醚萜及其衍生物调控自噬作用机制，并结合生物信息学、分子生物学等技术，阐明熟地黄治疗帕金森病的物质基础及分子机制，构建熟地黄环烯醚萜类衍生物与PD在诱导自噬通路上的活性成分-靶点网络。该项目研究期间：作为通讯作者共发表基金号标注的SCI收录的研究论文10篇，影响因子>5的论文共7篇；申报专利2项；培养硕士研究生10人；联合培养博士研究生5人；2019年获得四川省科技进步一等奖。完成了预期的研究目标。