The Molecular Simulation And Design Of High Activity Drug Lead Compounds

Traditional drug discovery is not only time-consuming but also randomness and blindness. With the continuous development of computer science, biochemistry and other interdisciplinary, molecular simulation gradually replaces the traditional drug discovery, and drug discovery has gone into a new era. In this dissertation, the techniques of molecular simulation were used to analyze the therapeutic mechanisms about two types of high activity drug lead compounds (aggrecanase-2and anti-HBV inhibitors), respectively. And then several new drug lead compounds with higher activity were designed. Additionally, the toxicity of halogenated phenolic compounds was researched and new compounds with low-toxicity were designed.The first chapter briefly described the background of molecular simulation, and the methods of two-dimensional quantitative-structure activity relationship (2D-QSAR) and three-dimensional quantitative-structure activity relationship (3D-QSAR) were introduced. Molecular docking was also presented at the same time. Finally, a summary of the main work of this dissertation was listed briefly.The second chapter analyzed the inhibitors of osteoarthritis by3D-QSAR and molecular docking methods. Osteoarthritis is a high incidence disease and difficult to cure, so it brought patients with long-term illness. Researchers found that aggrecanase-2was the potential drug target, and a series of inhibitors that against aggrecanase-2were studied. A model was established between the structure of the inhibitors and the activity through3D-QSAR, and then the factors that affected the activity of the inhibitors were studied and demonstrated by molecular docking. In the end, some new drug lead compounds with higher activity were designed based on the factors that obtained.The third chapter analyzed the interaction patterns between HBV nucleocapsid protein and three types of anti-HBV drugs by means of molecular docking, and the specific interactions between HBV protein and three types of molecules were obtained, then "parachute" model was put forward. Finally, one type of drugs was analyzed with3D-QSAR, and some important factors that affected the activity of the compounds were obtained and confirmed by molecular docking.The forth chapter analyzed the toxicity of halogenated phenolic compounds through2D-QSAR and3D-QSAR methods. Halogenated phenolic compounds polluted environment severely, which are difficult to degradation and can pose a serious health hazard to lives. Three models, which presented the relationships between the toxicity of halogenated phenolic compounds and their structures, were established in this work, and the factors that influenced the toxicity of the compounds were also analyzed. Based on the factors, some new halogenated phenolic compounds with low-toxicity were designed.