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

这项授予肯特大学的EPSRC案例奖学金将与DSTL合作开发基于核磁共振的筛选方法，以获得关键化合物(包括有机磷)与人类AChE的结合亲和力和特定结合模式分析。AChE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醋酸。该项目的关键目的是了解人类AChE抑制剂驱动的分子过程，以促进针对这些化学物质的预防性药物的设计过程。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核磁共振方法的发展，以研究配体-蛋白质结合模式和亲和力，从而启发我们对AChE抑制剂的理解。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，此外在利用核磁共振光谱学表征蛋白质-配体相互作用方面具有世界领先的能力。除了研究有关乙酰胆碱酯酶的极端生物学和生物医学兴趣的领域外，这也将培训在高级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.