Menin蛋白与MLL融合蛋白的相互作用界面被认为是一类理想的白血病治疗靶标，基于蛋白-蛋白相互作用开展药物设计是目前研究的重点和热点。由于目前报道的menin-MLL小分子抑制剂骨架单一、类药性不佳，多肽类抑制剂尚未见报道。因此，寻找新的menin-MLL抑制剂十分必要。本研究将基于我们建立的menin-MLL虚拟筛选平台和分子及细胞水平的实验平台，筛选小分子和多肽类抑制剂，同时进一步优化并完善已建立的抑制剂筛选与评价平台。我们将综合运用分子对接、药效团模型、骨架跃迁、靶向集中组合库、蛋白-蛋白对接、关键残基嫁接、构效关系研究等分子设计及结构优化方法，结合有机合成、分子生物学和药理学等实验方法，加速药物设计并获得全新、活性高、类药性佳的menin-MLL抑制剂，为抗白血病提供新的药物先导结构，为开发具有自主知识产权的创新药物奠定基础。本申请项目拟发表SCI论文2-3篇，申请专利1-2项。

The menin-MLL fusion protein interface, which is a form of protein-protein interactions (PPI), represents an attractive therapeutic target in acute leukaemia. Drug design targeting PPI has became a subject of intense activity in drug discovery. However, to date, the small molecule inhibitors against menin-MLL interface shares the same scaffold, with poor drug-likeness, the peptide inhibitors have not been reported. Thus, it is necessary to develop novel menin-MLL inhibitors. In our study, we have established the virtual screening models against menin-MLL interface, as well as the molecular and celluar levels of experimental platform, to identify menin-MLL inhibitors. Further optimization of menin-MLL inhibitors screening platform would be carried on. Through the combination of molecular docking, pharmacopore models, scaffold hopping, focused combinational library design, protein-protein docking, key residues grafting, synthesis, molecular biology and parmacology methods, more small molecule and peptide inhibitors with novel scaffolds and good pharmaceutical properties are expected. This study will light on the development of powerful probes and new therapies for MLL-mediated leukaemogenesis. We plan to publish 2-3 papers in SCI and apply for 2-3 patents.