中药天然药物中抗老年痴呆活性成分作用机制及成药性研究

On the basis of plenty previous studies, the aim of the present project is to investigate the potential bioactive fractions/components from Chinese natural medicines, which were proved to show good anti-dementia effects in previous in vivo or in vitro studies. For bioactive fractions, a variety of dementia animal models would be applied for further pharmacodynamics evaluation. The druggability of those bioactive fractions would be estimated based on the clarification of the components, revelation of their pharmacokinetics and efficiency. For some bioactive fraction with toxicity, the research of toxicity-guided components isolation and function-toxicity confirmation would be carried out to evaluate their druggability. For a large number of active compounds achieved from previous studies, structure-based virtual screening would be applied to predict their molecular targets related to anti-dementia function. The structures and functions of those predicted targets would be further validated and those potential compounds would be put through further pharmacodynamics and druggabilty studies. The aim of the present study complies with national requirements since anti-dementia drugs are in great need of Chinese people. Taking Chinese natural medicines as breakthrough point, the research will be performed by close cooperation between chemists and biologists from different levels, and thus this research will be labeled with strong Chinese characteristics. Results obtained from this project are expected to provide innovative research methods for new drug discovery based on Chinese natural bioactive components, and are of great significance for Chinese medicine modernization.

本项目在前期大量研究基础上，将聚焦从中药中获得、经过体内/外生物活性测试初步确认有较好功效的抗老年痴呆活性部位/活性单体进行深入研究。对活性部位，将采用多种AD整体动物模型确认药效，并在进一步阐明成分、体内过程与功效的相关性基础上，探讨其成药性；对活性很好、但同时表现有某种毒副作用的活性部位，将深入研究其中所含成分，分析它们与活性/毒副作用的相关性，探讨其成药性；对前期工作中积累的大量单体活性化合物，将采用计算机反向筛选技术，从分子水平开展预测抗AD作用靶点，并对预测的靶点进行功能验证，快速寻找具有成药前景的活性分子，再进行药效学和成药性研究。本项目探索老年痴呆疾病的防治药物，方向符合国家和社会的重大需求；以传统中药天然药物为切入点，实行化学-生物学紧密结合攻关，从不同层次开展研究，体现中国特色；研究结果对探索基于中药天然药物活性物质的创新药物研究方法及对中药现代化均具有重要意义。

老年痴呆症是威胁人类健康的重大疾病之一，是全球性公共卫生问题。由于疾病自身发病机制的复杂性，导致其早期成药性评价存在困难。本项目针对长期困扰中药新药早期成药性研究的主要科学问题，开展多层次系统研究，建立了基于老年痴呆症的中药新药早期成药性评价关键技术体系；以“栀子藏红花素富集部位”为研究示范，开展了药材来源、化学成分确证、质量标注制定、药效学及作用机制、早期安全性评价以及非临床药代动力学等研究工作，初步获得了1个具有良好成药性的中药新药1.2类候选药物。项目建立的基于老年痴呆症的多维药效学评价体系等成药性研究关键技术，为老年痴呆中药新药研发提供了借鉴和参考，对其他复杂疾病领域的创新药物研究具有示范作用和积极意义。