抗菌肽(AMP)具有抗菌谱广、耐药性低等系列优点，但开发利用受其特异性毒性制约，因而提高选择性是解决其临床应用的关键。本研究针对AMP的特异性毒性，以小分子抗菌拟肽为研究对象，基于天然AMP及其类似物的构效关系研究，建立理论预测模型指导抗菌拟肽的合理设计与虚拟筛选；应用分子模拟方法分析拟肽与真核及细菌细胞膜间的相互作用差异，构建拟肽对细胞膜选择性作用的理论预测模型；通过稳定性与抗菌实验筛选活性拟肽分子，基于膜脂质翻转与去极化实验，验证拟肽以细胞膜为靶标的作用机制；采用脂质膜染料渗漏、体外溶血及细胞毒性实验，评价拟肽的选择性。本研究不仅可为拟肽的合理设计与高效筛选建立完整技术方案，筛选获得抗菌活性强、稳定性好、选择性高、耐药性低的活性拟肽分子，而且能够基于拟肽的构效与构毒关系研究结果，从分水平揭示拟肽的抗菌作用机制及其产生特异性毒性的本质与一般规律，为高选择性抗菌拟肽的研究与开发奠定基础。

Antimicrobial peptide (AMP) has numerous advantages, such as broad antimicrobial spectrum and low drug resistance, but the AMP-specific toxicity hinders its practical uses severely. Therefore, promoting the selectivity of AMP is the basis for its clinic applications. In this study, the small peptoids is explored for their innate toxicity. First, the scheme of rational design and high throughout screening of antimicrobial peptoids will be explored, which is based on the quantitative structure-activity relationship modeling of natural AMPs and their analogues, and the theoretical model of membrane-based selectivity for the peptoid will be constructed, which is based on the molecular modeling of the interaction between the peptoid and the membrane of bacterial and eukaryotic cell. Secondly, the active peptoids are screened by the experiments of stability and antimicrobial activity, and the mechanism of membrane-targeting is validated through the membrane lipid flip-flop and penetration methods. Finally, the experiments of dye leakage of lipid membrane, hemolysis and cytotoxicity are used to evaluate the selectivity and safety of the active peptoids. This study may establish the technical scheme of the rational design, theoretical prediction and high performance screening for the AMP and its analogues，and the active peptoids with high antimicrobial activity, stability, selectivity, and low drug resistance would be screened. Meanwhile, the theoretical models of structure-activity and structure-toxicity of the peptoid will be built, which are used to explore the mechanism of antimicrobial activity and general rule of AMP-specific toxicity. In general, this study will becomes the basis of research and development of antimicrobial peptoids with selectivity