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

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.

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。

脂肪酸生物合成是细菌生物膜形成的必经过程，抑制其合成过程就干扰了生物膜的形成，就起到了抑制细菌生长和繁殖的作用。基于细菌和人类代谢过程中脂肪酸合成途径的酶无同源性，且该途径中酶系独特、靶点丰富，依据代谢途径分析可从细菌代谢途径中发现一系列理想的抗菌作用靶标。根据功能性、必要性以及对人体无毒性等要素，选取细菌脂肪酸合成系统的FabI、FabH、FabB、FabG、FabF等蛋白及细胞分裂蛋白FtsZ等酶作为靶标。首先，应用分子动力学模拟、DSSP和POVME计算方法，分别研究了各个靶标及其经典抑制剂的复合物体系中活性口袋loop区构象、loop区二级结构、活性口袋体积以及底物通道等随模拟时间的变化规律，揭示了抑制剂分子与靶标酶的作用规律和机制。其次，运用相似性搜索和类药性初筛方法建立了小分子数据库，以靶标蛋白为受体，采用虚拟筛选、一致性对接和一致性打分，筛选了具有高效抑制作用的化合物，系统分析了它们与靶标蛋白的结合模式及相关规律，对筛选的部分候选化合物及中间体进行了全合成和绿色合成研究。此外，基于FabI、FabH、FabB、FabG、FabF等系列靶标（靶标实验室）和选定的一些核心分子骨架，开展了基于多靶标的新型抑制剂分子设计筛选方法学研究。

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