Developing Cholinesterase (AChE) inhibitor screening methods using Nuclear Magnetic Resonance Spectroscopy (NMR)

肯特大学与DSTL合作，将开发基于核磁共振的筛选方法，以获得包括有机磷酸盐在内的关键化合物与人类乙酰氨基甲酸酯的结合亲和力和特定结合模式分析。乙酰胆碱酯酶主要位于神经肌肉连接处、神经突触和红细胞膜上，属于胆碱酯酶家族，可催化神经递质乙酰胆碱水解成胆碱和乙酸。该项目的主要目的是了解人类乙酰胆碱酯酶抑制剂驱动的分子过程，以促进这些化学物质的预防剂的设计过程。需要掌握的技能包括核磁共振波谱、生物信息学、酶生化和生物物理蛋白质表征。主要驱动因素将是开发特定的核磁共振方法来研究配体-蛋白质结合模式和亲和力，从而启发我们对乙酰胆碱酯酶抑制剂的理解。项目监督将由Dr. Mark Howard（肯特）和Dr. James Jones （DSTL）提供。项目合作伙伴在生物信息学、蛋白质表达、纯化和表征方面拥有国际水平的专业知识，此外在利用核磁共振光谱表征蛋白质与配体相互作用方面也具有世界领先的能力。除了研究与乙酰氨基甲酸酯相关的极端生物和生物医学领域外，这也将培养在先进生物和工业核磁共振光谱中的成功应用。

This EPSRC CASE studentship awarded to the University of Kent, in association with DSTL, will develop NMR-based screening methods to obtain binding affinities and specific binding mode analyses of key compounds, including organophosphates, to human AChE. AChE is primarily located in neuromuscular junctions, neural synapses and on red blood cell membranes and is from the family of cholinesterase enzymes that catalyse the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid.Key aims of the project are to understand the molecular processes driven by inhibitors of human AChE to facilitate the design process of preventative agents to these chemicals. Skills to be gained include NMR spectroscopy, bioinformatics enzyme biochemistry and biophysical protein characterisation. The primary driver will be the development of specific NMR approaches to study ligand-protein binding modes and affinities that enlighten our understanding of AChE inhibitors. Project supervision will be provided by Dr. Mark Howard (Kent) and Dr. James Jones (DSTL). The project partners have international-level expertise in bioinformatics, protein expression, purification and characterisation in addition to a world-leading competence in the use of NMR spectroscopy in characterising protein-ligand interactions. In addition to researching an area of extreme biological and biomedical interest regarding AChE, this also will train the successful application in advanced biological and industrial NMR spectroscopy.