基于细菌脂肪酸合成途径中多靶标的新型抗菌剂设计开发

发现新作用机制、研制新型抗菌剂是解决人类面临的旧传染病复燃、新传染病迭出、病原体耐药性增加三大难题的重要途径。解析细菌代谢网络寻找抗菌新机制和作用靶点，借助计算机辅助设计开发新型抗菌剂，已成为抗菌药物研究的前沿领域。 依据代谢途经分析，人类和细菌代谢过程中脂肪酸合成途径的酶无同源性，且该途径酶系独特、靶点丰富，是抗菌作用靶标的理想源。本课题拟依据生物信息学理论，采用计算机模拟方法对病原菌脂肪酸合成途径的关键酶进行数据挖掘和处理，用代谢途径及基因比较、蛋白质结构预测、分子模拟等方法识别确认作用靶标及其活性位点，用分子对接、分子动力学模拟、3D-QSAR等方法研究抗菌剂与靶点的结合模式、作用机制及定量构效关系。同时研究多靶点协同下的受体-配体作用规律，编制多靶点抗菌剂设计筛选策略方法。设计筛选一批候选化合物并进行制备及抗菌活性研究。构建基于细菌脂肪酸合成途径中多靶标协同的新型抗菌剂创制平台。

Discovery of new mechanisms and development of novel antibacterial agents are the basic ways to solve the three problems, the resurgence of old infectious diseases, the emergence of new infectious diseases and the drug-resistant pathogens, which mankind is confronted with. Analyzing the bacterial metabolic networks to reveal new antibacterial mechanisms and novel antibacterial targets and then using Computer-Aided Drug Design to discover novel targeted antimicrobial drugs have become a frontier research. According to the analysis of metabolic pathways, the fatty acid synthetase in human shares no striking primary sequence homology with that in bacterium, and this metabolic pathway involves many unique enzymes that make them act as idea source of targets for antibacterial agents. This project intends to perform data processing and mining for the key enzymes of the metabolic pathway by computer simulation methods according to the theories of bioinformatics, and then identify antibacterial targets and their active sites by comparison of metabolic pathways and genes, prediction of protein secondary structures and the molecular simulation methods, etc. Molecular docking, molecular dynamics simulation, 3D-QSAR and other methods will be adopted to study the binding modes between the ligands and the targets, the mechanisms of action and the quantitative structure-activity relationship. At the same time, we will study the action rules of the receptors and ligands under the synergistic effect of multi-targets to develop the strategies for designing and screening of multi-target antibacterial agents. And then the preparation and detection of antibacterial activity of these candidate compounds will be performed. Eventually, we will construct a platform to develop novel multi-targeted antibacterial agents based on the fatty acid synthetase pathway.