A Study On The Methodology And Key Technology For Designing Modern Chinese Medicine

Traditional Chinese medicine (TCM) is a great treasure-house in China, which has become important resources for drug discovery and design. Nowadays, there are three major strategies for the development of Chinese medicines from TCM. The first strategy is to manufacture botanical drug from clinically therapeutical prescription by traditional preparation techniques. The second method is to isolate, screen and identify active components or chemical compounds from TCM, which can be used as herbal medicine. The third approach is to develop new drug from already marketed drugs by changing the formulation or clinical use. However, the technological levels of those methods are relatively low, especially lacks of appropriate methodology and key techniques for drug design. Therefore, the establishment of new technology for drug discovery and design has become pivotal industrial demands and scientific research project in Chinese pharmaceutical fields.The major challenges in the discovery and design of modern drug from TCM includes three major problems, i.e. how to discover active components from TCM, how to design optimal combination of active components, and how to dissect the chemical composition and exact mechanism of action of those components. In this dissertation, a series of techniques were established aiming to solve those problems in the drug development pipeline of modern Chinese medicine. By integrating multi-disciplinary technologies from analytical chemistry, biochemistry and computer sciences, novel methodology and techniques for the design of modern Chinese medicine have been established. The proposed methods have been successfully applied in the re-discovery of many traditional prescriptions including Qi-Xue-Bing-Zhi-Fang, Shuangdan Decoction, and Compound Danshen, which indicated a new mode for the development of multi-component drug using active components of traditional formulae. The major results obtained from the study have been described as following:1. A novel method was proposed to identify active components of TCM. This method used a stepwise causal adjacent relationship discovery algorithm to analyze correlation between the composition and bioactivity of TCM. Integrated with phytochemical analytical and bioassay techniques, causality discovery algorithm can find out active components from the complex mixture. Successful applications of this method have been performed in discovering anti-cancer compounds from mixture of ginsenosides, cardio-protective compounds from Shuangdan Decoction, and identifying components combination with decreasing total cholesterol activity from Qi-Xue-Bing-Zhi-Fang. The results indicated that the present method can accurately discover active components or compounds based on the composition and bioactivity data of TCM, which offers a new way to screen active components from TCM.2. The strategy for designing multi-component drugs from TCM was developed by modeling quantitative composition-activity relationship (QCAR). The computational models characterized the relationship between chemical composition and their activities of components, which can be used to predict activity of all possible combination of components and to select the optimal combination of multiple active components by exhaustive searching and genetic algorithm. This approach was successfully applied in finding optimal combination of two active components of Qi-Xue-Bing-Zhi-Fang. Validation experiments showed that the optimized combination has greater activity than original remedy, which implies that the presented method is an efficient approach for the design of botanical drug from TCM.3. The analytical approach for the pharmacoproteomics study of TCM was established. The proposed comparative proteomic approach was applied to investigate the potential mechanism of action for cardioprotective effects of Shuangdan Decoction (SDD) on ischemic rat heart. Twenty-three altered proteins were identified. Those proteins included eleven proteins related to energy metabolism process, such as respiration chain, TCA-cycle, andβ-oxidation. Moreover, some proteins linked to oxidative stress such as SOD and Hsp27 were also found to be regulated by SDD. Functional analysis of the differentially expressed proteins suggested that SDD diminished ischemic-induced damage through promoting myocardial energy status and reducing oxidative stress.4. Cardioprotective effect of Compound Danshen on coronary artery ligated rats has been studied by the proposed proteomic approach. Thirty-two differentially expressed proteins were identified. Moreover, expression of heat shock protein 27 (Hsp27) and related post-translational modifications (PTMs) induced by Compound Danshen were further studied. The results suggested that the mechanism of action of Compound Danshen was related to the improvement of energy metabolism, recovery of mitochondrial function, and the depressing of oxidative stress induced injury in ischemia myocardium.