中药靶标活性谱的构建及其在降血脂有效成分配伍中的应用研究

The study on the clarification of the material basis and action mechanism of Chinese material medica (CMM) is the core tasks of the modernization of CMM. Meanwhile, the study on the combination of Chinese herb components significantly marks the direction of new drug design of CMM. The key issue in the studies mentioned above is how to enhance the whole function through rational compatibility of CMM components, as the individual component could act on multiple protein targets and every single target constantly interact with many components..Accordingly, this research proposes a novel method, namely CMM-target effects relationship spectrum, which uncovers the relationship between effective ingredients and targets. The relative interaction strength would be determined, as well as the standard procedures to rapidly construct the spectrum would be established. With hyperlipidemia and lipid-lowering traditional medicine as the research carrier, the techniques and methods including molecular simulation, network pharmacology approach, data mining and optimization algorithm will be combined with high throughput screening, high content screening and animal experiments to construct CMM-target effects relationship spectrum for anti-hyperlipidemia. The active herb composition and relative key target will be identified and the synergetic mechanism of targets will be discovered. The method established in this project can be used to guide compatibility, to optimize proportion of herb composition and to design new CMM drugs which have definite action mechanism and significant therapeutic effect. Therefore, the research on the construction of traditional Chinese medicine-target effects relationship spectrum and their applications will promote the development of CMM modernization fast and efficiently and provide guidance for multi-fractions traditional Chinese medicine design.

明确中药药效物质与作用机制是中药现代化研究的核心任务，而组分配伍研究是现代中药新药创制的重要方向。中药单一成分可作用于多个靶点，每个靶点也有多个成分发挥作用，多成分如何有效配伍实现中药整体效用，仍是上述研究中的关键科学问题。.针对这一问题，本研究提出“中药靶标活性谱”概念，建立了用于表达各有效成分作用靶标与相对作用强度的中药靶标活性谱快速构建方法。本项目以高脂血症及降脂中药/方剂为研究载体，以分子模拟技术、生物网络构建和分析技术、数据挖掘和寻优算法等为主要研究方法与技术，与高通量/高内涵筛选、整体动物药效实验相结合，建立中药降脂靶标活性谱，辨识中药降脂有效成分及其降脂关键靶点，发现其共性靶标组合，优化中药降脂药效成分配伍配比，设计作用机理明确、疗效显著的降血脂中药新药。本项目所建立的中药靶标活性谱有助于为中药作用机理解析和物质基础研究、组分中药创制提供研究思路与技术方法。

本研究严格按照申请书的研究目标开展研究，朝向作用机制明确的中药药效物质组分配伍的新药创制。以高脂血症和血栓为研究载体，结合计算机辅助药物设计多种方法、数学模型和药理学的研究成果和技术手段，创新性地融合不同模型的预测活性，构建中药靶标活性谱，并形成基于靶标活性谱的方剂精简方法。本课题构建了3个降脂相关靶标的6个虚拟筛选模型，以及6个抗凝血相关靶标的12个虚拟筛选模型，并构建了3种肠道吸收转运体的吸收模型用于预测中药成分的吸收入血性质。结合实验室前期构建的5个降脂靶标的10个虚拟筛选模型、1个抗凝血相关靶标的2个虚拟筛选模型，共同构建靶标活性谱。创新性地采取了概率融合的方法，将同一靶点的多种模型筛选结果进行融合。使预测结果可反映多个虚拟筛选方法结果，提高结果的准确可靠性。融合结果用于进行靶标活性谱的构建，分别构建了降脂靶标谱及抗凝血靶标谱。靶标谱可直观、全面的展示中药与相关靶标的相互作用关系及强度。基于靶标谱提供的相关信息，进一步探讨了精简方剂方案的设计方法，并对抗凝血的经典名方桃红四物汤和血府逐瘀汤进行了方剂精简，共提出4种方案，并通过体内实验，对4种方案进行活性评价，初步获得能较好代表原方剂抗凝血活性的精简方剂。.本课题研究期间发表论文26篇、其中SCI论文11篇；已毕业硕士研究生8名。研究所提出的中药靶标活性谱为可视化、定量化的描述和研究中药多成分-多靶点相互作用提供了新的技术方法，为进一步进行中药活性成分筛选分析和中药方剂精简提供了有力工具。