Flavonoids And Other Three Kinds Of Drugs Synthesis And Molecular Simulation

Investigations of drug synthesis and the interaction mechanism between drugs and their targets have an important meaning in exploiting the new medicine and revealing toxicity mechanism of drugs into the organism. So it becomes one of the main means by using computer to assist and guide drug design and synthesis. In this thesis, we designed and synthesized a series derivatives of flavonoids and antidepressant venlafaxine, tasted the biological activity of some of new compounds. In order to reveal the interaction mechanism between compounds and target protein, we studied new compounds with molecular .simulation. In addition, because of heart toxic side effect of most fluoroquinolones drugs, people can die when this effect is serious, but the toxicity mechanism of fluoroquinolones is not clear, so we studied the toxicity mechanism between fluoroquinolones and potassium ion channel protein by using molecular simulation, exploring mechanism of toxic side effect in human heart ar molecular level. The whole dissertation was divided into four chapters as follows:The first chapter: Summarizes application of the molecular simulation in drug synthesis, the research progress of flavinoids, antidepressants and fluoroquinolones and expounded the mainly content and selection basis of this thesis.The second chapter:Put forward a new skeleton total synthesis route of flavonoids, synthesized twelve new flavonoids and identified their structure. Molecular simulation of them were performed to explain the mechanism between drug and target, results showed that 4-carbonyl group of molecular of flavonoids is the key group which interacted with caspase-3 protein,5’position of flavonoids is the important replace bits forming hydrogen bonds between drugs and target, the effect of interaction is markedness if substituents are bases of proton, for example -NO2. The result of molecular simulation can provide theoretical basis for further research of this kind of drug.The third chapter: we designed and synthesized a series of antidepressant venlafaxine derivatives, evaluated their activities of antidepressant with experiments. Biological tasts showed that activity of 10 derivative was the best one. (IC50=218 nM) Moreover molecular simulation was performed to find the interaction mechanism between venlafaxine derivatives and 5-HT retaken protein. The study found that the result of activity test was consistent with result of molecular simulation, the result of molecular simulation showed that hydroxyl of venlafaxine was the key pharmacophores. The fourth chapter:we studied the interaction mechanism between several typical fluoroquinolones drug and K+channel protein with method of .molecular simulation, the result showed that it was more probability of forming hydrogen bond between carboxyl of fluoroquinolones and amino acid residues of K+channel protein. so carboxyl was the key group. We could get that SER272, SER247, SER344 and SER53 were the key amino acid residues around activity pocket when drugs bind to target.