Acquisition of 700 MHz NMR for Automated Chemical/Peptide Library Screening

描述(由申请人提供)：为布鲁克Avance III 700 MHz核磁共振光谱仪申请资金，该光谱仪配备了低温探头和Tecan机器人，用于全自动化合物文库筛选，以支持一个研究财团的生物医学研究。基于核磁共振的筛选是非常通用的：适用于广泛的靶标和化合物文库以及配体结合亲和力。因此，它对药物发现和新药进入临床产生了重要影响。核磁共振筛选是对传统高通量筛选技术的补充，允许HIT验证和优化(提供关于结合模式的结构信息)。所要求的仪器将对达特茅斯学院、达特茅斯医学院和诺里斯·科顿癌症中心以及包括佛蒙特州大学医学院、马萨诸塞州大学、蒙特利尔大学和康涅狄格大学健康科学中心在内的地区性大学的参与教员的生物医学研究产生直接影响。项目包括抑制重要信号转导级联中的关键蛋白质-蛋白质相互作用，筛选竞争性和变构酶抑制剂，以及对天然产物进行合理修饰的结构洞察。该仪器将构成一个筛查设施的基础，该设施将安装在达特茅斯园区正在建设的一座新的生命科学大楼中。对这一设施额外支助包括一名核磁共振技术员的工资以及最近征聘的两名研究科学家：一名在利用核磁共振进行文库筛选方面有8年以上的工业经验，另一名在合成化学方面具有专门知识，用于精制HITS或优化片段的连接。有了这些专业知识，几乎没有筛查或核磁共振经验的生物医学研究人员就可以很容易地使用该设施。对设施运作的监督将由一个由三名主要用户组成的咨询委员会保证。已经成立了一个由核磁共振筛选领域的主要专家组成的外部咨询委员会，以协助优化利用该设施和应用正在开发的技术。 公共卫生相关性：所要求的仪器和筛查设施将提供 将基础生化发现转化为癌症、囊性纤维化、炎症、骨质疏松症和药物成瘾分子干预的主要候选者的重要数据。

DESCRIPTION (provided by applicant): Funding is requested for a Bruker Avance III 700 MHz NMR spectrometer equipped with a cryogenic probe and Tecan robot for fully automated compound library screening to support the biomedical research of a consortium of investigators. NMR-based screening is extremely versatile: applicable to a wide range of targets and compound libraries as well as ligand binding affinities. As such it has made an important impact on drug discovery and progressing new medicines into the clinic. NMR screening complements traditional high-throughput screening technologies allowing for hit validation and optimization (providing structural information on the mode of binding). The requested instrument will have an immediate impact on the biomedical research of the participating faculty from Dartmouth College, Dartmouth Medical School and the Norris Cotton Cancer Center and regional universities including University of Vermont Medical School, University of Massachusetts, University of Montreal, and University of Connecticut Health Science Center. Projects include inhibition of key protein-protein interactions in important signal transduction cascades, screening for competitive and allosteric enzyme inhibitors, and structural insight for rational modification of natural products. The instrument will form the basis of a screening facility to be housed in a new life sciences building under construction on the Dartmouth campus. Additional support of this facility includes that salary of an NMR technician as well as the recent recruitment of two research scientists: one with over 8 years of industrial experience in the utilization of NMR in library screening and a second with expertise in synthetic chemistry for elaboration of hits or tethering of optimized fragments. With this expertise available, the facility will be readily accessible to the biomedical researcher with little screening or NMR experience. Oversight of the facility operation will be guaranteed by an advisory committee of three of the primary users. An external advisory committee of leading experts in NMR screening has been formed to assist in optimal utilization of the facility and application of developing technologies. PUBLIC HEALTH RELEVANCE: The requested instrument and screening facility will provide vital data to translate fundamental biochemical discoveries into lead candidates for molecular intervention for cancer, cystic fibrosis, inflammation, osteoporosis, and drug addiction.