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

描述（由申请人提供）：本提案寻求资金，用于购买配有适当软件的ThermoFisher Q-Exactive快速扫描高分辨率质谱仪，该质谱仪将成为药物代谢和药代动力学（DMPK）核心的一部分，专门用于体外和动物中小分子处置研究。这一共享工具将扩大能力，并支持来自七个机构的十六个NIH资助项目的一系列研究项目。这些项目中的每一个与DMPK核心的参与程度都很高，这可以通过相应赠款中的财务承诺来证明，以支付部分技术人员工资和实验费用（16名研究者中的13名）或通过专门写入赠款的退款（16名研究者中的3名）。我们提出了购买Q-Exactive质谱仪系统的理由，证明使用高分辨率质谱法进行代谢实验获得的信息内容显着增加。采用这一新技术可以从复杂样品中同时获取高性能的定性和定量数据。Scripps DMPK核心中的当前质谱仪是三重四极杆仪器，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度，这对于表征未知代谢物至关重要。按照Scripps佛罗里达标准制备样品，并将其发送给三家供应商的应用专家，以评价ThermoFisher Q-Exactive、ABSciex 5600 tripleTOF和沃茨Synapt G2 QTOF。所提供的数据表明，每个主要用户将从现有设备目前无法实现的高分辨率质谱仪中获得好处。数据也提出了合理的选择的Q-Exactive超过其他优秀的系统。受益于共享工具的大部分赠款是探针优化，转化科学和药物发现赠款。在优化阶段，阐明单个化合物的代谢责任的能力的显著增加将提高项目的生产力。化合物优化是一个迭代过程，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能。这台共享仪器将安装在斯克里普斯佛罗里达质谱实验室，并由一组经验丰富的质谱师、PI和两名高级研究技术人员进行维护。几名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.