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

授予肯特大学的EPSRC CASE学生奖学金将与DSTL合作，开发基于NMR的筛选方法，以获得关键化合物（包括有机磷酸酯）对人类乙酰胆碱酯酶的结合亲和力和特异性结合模式分析。乙酰胆碱酯酶主要位于神经肌肉接头、神经突触和红细胞膜上，属于胆碱酯酶家族，催化神经递质乙酰胆碱水解为胆碱和乙酸。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，以促进预防这些化学物质的设计过程。将获得的技能包括核磁共振光谱学，生物信息学酶生物化学和生物物理蛋白质表征。主要的驱动力将是特定的NMR方法的发展，研究配体-蛋白质结合模式和亲和力，启发我们的理解乙酰胆碱酯酶抑制剂。项目监督将由马克霍华德博士（肯特）和詹姆斯琼斯博士（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NMR光谱表征蛋白质-配体相互作用方面也具有世界领先的能力。除了研究关于乙酰胆碱酯酶的极端生物学和生物医学兴趣的领域外，这也将训练在先进的生物和工业NMR光谱学中的成功应用。

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.