Fragment-Based Drug Discovery Library based on Ligusticum Chuanxiong, a Traditional Chinese Medicine

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Quinn, Ronald J

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Liu, Miaomiao

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Traditional Chinese Medicine (TCM) is a valuable source of chemical and structural diversity discovery, who has thousands of years of history. In long-term clinical practice, it generated more than 1,000 commonly used TCMs and prescriptions with exact curative effects and high safety. Researchers have made many efforts over the past few decades, from finding a single active compound to identifying a combination of compounds. The successful discovery of artemisinin and salvia are good samples. Fragment-based drug discovery is a method to design and establish a compound library composed of fragments, and to screen the compounds for biological activity. The X-ray crystallography, nuclear magnetic resonance and mass spectrometry were used to analyse the binding mode and binding strength of these fragments and target proteins, and based on the structural information, the structure of the fragment molecules was optimised to obtain lead compounds. Owing to the success of TCM in the drug discovery area, the main aim of this project was to chemically investigate the small molecules produced by the selected TCM—Ligusticum Chuanxiong. This project is part of an effort to modernise TCM and will involve assessing low Molecular Weight TCM constituents by the relatively new Fragment-Based Drug Discovery technique. Two libraries, a fragment library isolated from Chuanxiong and a virtual fragment library from the Literature were constructed and their chemical diversity were evaluated by self-organizing map (SOM). In this study, we have also used Magnetic Resonance Mass Spectrometry (MRMS) to perform a targeted screening of the constructed TCM fragment library against three tuberculosis proteins. This project presents efforts to achieve an effective approach to discover TCM by analysis two kinds of libraries based on Fragment-Based Drug Discovery (FBDD). The first chapter introduced the history and development of TCM, FBDD theory for building a library. Based on these backgrounds, the idea of building a TCM based FBDD library was generated. It also covers a review on structure diversity analysis and target identification, which used as the approaches to evaluate the libraries. The results are presented in chapters 2 to 4. Chapter 2 presents the whole process of extraction and isolation of a TCM Chuanxiong by different chromatographic methods. Structures of the isolated compounds were determined by NMR and MS data. A fragment library of eight compounds as well as a “peak” library, were obtained and analysed. Chapter 3 describes the diversity analysis of the virtual Chuanxiong fragment library using self-organizing map (SOM). The library consists of 122 reported low molecular weight (MW) compounds. With the aim to test the diversity of this library, eight 2525 sized SOMs and four 1010 sized SOMs were generated against an existed natural product library containing 20,185 low MW compounds. Chapter 4 presents the FTMS analysis for 3 tuberculosis (TB) proteins. The “peak” library in chapter 2 was screened against the 3 TB proteins. Unfortunately, no protein-ligand complex was observed. The thesis is a brief process for TCM based FBDD research. For valuable TCM, it is able to isolate and generate libraries, which represent a large chemical space for target identification. It can be used for future drug discovery.

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Thesis (Masters)

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Master of Science (MSc)


School of Environment and Sc

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Traditional Chinese Medicine

Fragment-Based Drug Discovery

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