An interdisciplinary pipeline for progressing cyclic peptides hits to small molecule inhibitors.

研究问题和目标：通过多种方法可以很容易地针对给定的目标产生肽大周期命中，然而，将这些分子进展为药物样实体已被证明是极具挑战性的。我们在这个项目中的主要目标是将环肽蛋白-蛋白质相互作用抑制剂从hit转化为lead。方法：我们将使用化学生物学和计算化学相结合的方法来确定环肽与目标蛋白的结合位点，并开发更有效的小分子。我们的主要目的是确定活性分子的药效团，并利用这些信息来获得小分子抑制剂。同时，我们将通过加入非天然氨基酸和改变肽主链来优化环肽的活性。新颖的物理科学内容：满足上述目标将需要开发跨计算化学和化学生物学边界的跨学科工具管道。这包括开发模拟环肽的新方法，更好地了解环肽与其靶点的相互作用，以及开发合成目标分子的合成化学方法。

Research questions and objectives:Peptide macrocycle hits can be readily generated against a given target via a variety of methods, however, progressing these molecules to drug-like entities has proven extremely challenging. Our key objective in this project is to convert a cyclic peptide protein-protein interaction inhibitor from hit to lead.The approach:We will use a combination of chemical biology and computational chemistry to determine the binding site of the cyclic peptide hit on its target protein, and develop more potent small molecules. Our primary aim will be to identify the pharmacophore of the active molecule and use this information to derive small molecule inhibitors. At the same time, we will optimise the activity of the cyclic peptide by incorporating non-natural amino acids and altering the peptide backbone.Novel physical sciences content:Meeting the above objectives will require the development of an interdisciplinary pipeline of tools the crosses the boundaries of computation chemistry and chemical biology. This includes developing new approaches to simulating cyclic peptides, gaining a better understanding of the interaction of cyclic peptides with their targets and developing synthetic chemistry approaches for the synthesis of the target molecules.