Mass spectrometry for small molecule profiling in the Scripps Florida DMPK core

描述（由申请人提供）：本申请寻求资金购买ThermoFisher Q-Exactive快速扫描高分辨率质谱仪，该质谱仪带有适当的软件，将成为药物代谢和药代动力学（DMPK）核心的一部分，致力于体外和动物体内小分子处置的研究。这一共享仪器将扩大能力，并支持来自7个机构的16个NIH资助项目的一系列研究项目。这些以DMPK为核心的每个项目的参与程度都很高，这可以从各自赠款中的财政承诺中得到证明，这些资助承诺涵盖了部分技术人员工资和实验费用（16名研究人员中的13名），或者通过专门写在赠款中的退款（16名研究人员中的3名）。我们提出了购买Q-Exactive质谱系统的理由，证明了使用高分辨率质谱法进行代谢实验获得的信息含量显著增加。结合这项新技术，可以同时从复杂样品中获取高性能定性和定量数据。目前Scripps DMPK核心的质谱仪是三极杆仪器，非常适合测定血浆或其他组织中的药物浓度，但缺乏高分辨率和质量准确性，这是表征未知代谢物所必需的。样品在Scripps Florida公司制备，并发送给三家供应商的应用专家，对ThermoFisher Q-Exactive、ABSciex 5600 tripleTOF和Waters Synapt G2 QTOF进行评估。所提供的数据表明，每个主要用户将从现有设备无法实现的高分辨率质谱结合中获得好处。数据也提供了合理的选择Q-Exactive在其他优秀的系统。受益于共享仪器的大多数资助是探针优化、转化科学和药物发现资助。在优化阶段，阐明单个化合物代谢负债的能力显著增加将提高项目生产率。化合物优化是一个迭代的过程，在早期阶段了解分子的药物代谢和药代动力学特性可以优化整个分子，而不仅仅是生物化学或细胞效力。这台共享仪器将安装在斯克里普斯佛罗里达质谱实验室，并将由一组经验丰富的质谱专家、PI和两名高级研究技术人员进行维护。几位博士后研究员将接受或继续接受有关该仪器的培训。

DESCRIPTION (provided by applicant): This proposal seeks funding to purchase a ThermoFisher Q-Exactive rapid scanning high-resolution mass spectrometer with appropriate software that will become part of the drug metabolism and pharmacokinetic (DMPK) core dedicated to the study of small molecule disposition in vitro and in animals. This shared instrument will expand capabilities and support a range of research projects originating from sixteen NIH funded projects from seven institutions. The level of engagement for each of these projects with the DMPK core is high as demonstrated by the financial commitments in the respective grants to cover portions of technician salary and experimental expenses (13 of 16 investigators) or through chargebacks that are specifically written into grants (3 of 16). We present justification for the purchase of a Q-Exactive mass spectrometer system by demonstrating significant increases to the information content obtained from metabolism experiments performed using high resolution mass spectrometry. Incorporation of this new technology allows for the simultaneous acquisition of high-performance qualitative and quantitative data from complex samples. The current mass spectrometers in the Scripps DMPK core are triple-quadropole instruments ideally suited for determination of drug concentrations in plasma or other tissues, but lacking high resolution and mass accuracy which are essential for the characterization of unknown metabolites. Samples were prepared as Scripps Florida and sent to application specialists at three vendors for evaluation of the ThermoFisher Q-Exactive, the ABSciex 5600 tripleTOF, and the Waters Synapt G2 QTOF. The presented data demonstrates the benefits each major users will derive from the incorporation of high resolution mass spectrometry that are not currently possible with existing equipment. Data is also presented to rationalize the choice of the Q-Exactive over the other excellent systems. The majority of the grants that benefit from the shared instrument are probe optimization, translational science, and drug discovery grants. Significant increases in capacity to elucidate metabolic liabilities of individual compounds during the optimization phase will increase project productivity. Compound optimization is an iterative process and understanding the drug metabolism and pharmacokinetic properties of molecules at an early stage allows the whole molecule to be optimized instead of just the biochemical or cellular potency. This shared instrument will be installed in the Scripps Florida Mass Spectrometry Laboratory and will be maintained by a group of experienced mass spectroscopists, the PI and two senior research technicians. Several Post Doctoral fellows will be trained or continue their training on this instrument.