金（山）银花“异质等效”的超分子客体特征研究

More and more disputes have happened to confront continuously since the separation of Lonicera japonica and Lonicerae flos in Chinese Pharmacopoeia in 2005. The chemical compositions of two medicines have certain differences, however, there is no differences in side effects and clinic application for nearly 30 years from collected by the pharmacopoeia. According to the evidence-based medicine theory ,both medicines are clinical equivalent, Based on the clinical medication regularities，such as “treatment of different diseases with same drug”and “treatment of the same disease with different drugs”,and combined with the supramolecular chemistry, it was inferred out the hypothesis: “When the two drugs are absorbed, distributed, metabolized and excreted in the blood, the “impringting templates” of acting on the targets molecular will be similar, and have parallel biological effect”. The project, by studying molecular topological parameters (molecular connectivity index, molecular group contribution,etc.) and imprinting experiments to explore the "imprinting template" characteristic, using network dynamics method to obtain the equilibrium constant of composition and effect targets, drawing the topological graph of component group and targets and analysing topology relation, clarifies the supramolecular guest feature of in Lonicera japonica and Lonicerae flos, in order to solve the dispute and pharmacopoeia records providing scientific basis.

金（山）银花（亦金银花和山银花）从2005版《中国药典》分列之后，纷争不断。两药从其化学成分研究来看确有一定差异，但自药典收载使用近30年来看，并未出现任何疗效、毒副作用差异的报道，按循证医学理论可认为两者临床等效。针对这一现象，根据中医临床常见的“同病异治”和“异病同治”的用药规律，结合超分子化学，推论出:“两药经ADME入血后，原成分及其代谢产物作用于靶点分子的“印迹模板”特征相似，产生相似的超分子生物效应”的假说。本项目通过金（山）银花体内外成分拓扑参数（分子连接性指数、分子基团贡献等）的分析，结合印迹实验和功能相关的药理学实验，探讨其成分“印迹模板”的特征；并运用网络动力学方法测、算各成分与效应靶点的作用平衡常数，绘制成分与靶点的拓扑图，分析其拓扑关系，阐明其与功效关联的超分子客体特征，为解决金（山）银花之争、提供药典收载科学依据奠定基础。

本项目基于中医药超分子“气析”理论，对金（山）银花清热解毒功效的超分子客体特征进行了研究。首次对文献中金（山）银花成分客体的0-8阶分子连接性指数进行了计算；采用HPLC-MS方法对金（山）银花水提液的211个客体成分进行了定性测定，并计算了其分子连接性指数；再对12产地的金（山）银花水提醇沉液HPLC指纹图谱进行了测定，获得了总量统计矩参数，其总量一阶矩分别为为8.81 ± 0.63 min，10.0 ± 0.32 min，总量二阶矩为18.7±2.58 min2，17.42 ± 2.02 min2，证明了两药材客体成分“印迹模板”无显著性差异；采用HPLC-MS法测定了金（山）银花水提液的体内代谢成分，证明两者的成分种类和含量确有差异，其总量平均分子连接性指数经t检验，示两者无显著性差异；所测9个客体成分的药动学行为确有差异，但整体药动学行为没有差异。进行了金（山）银花客体成分的体外交叉印迹实验，发现两者正丁醇溶解部位的合成印迹聚合物对绿原酸类客体的选择性吸附无显著性差异；运用已建立的中药四性数学模型测得金（山）银花的代谢焓分别为-133KJ/g，-78.2KJ/g，示两者均为寒性；进行了抑菌抗炎实验，计算其谱效动力学参数，证明两者体内印迹作用等效，其平均总量分子连接指数在0～2.20之间，超分子“印迹模板”相似；其抗炎作用的客体分子“印迹模板”特征可能主要为5-7个C构成的活性空间结构。从而较全面地验证了“异原等效”假说。