Automated metabolite identification

Clarke, N., Cox, K., Dunn-Meynell, K., Korfmacher, W., Lin, C. C., White, R. and Cayen, M., Strategies for Semi-Automated Metabolite Identification in Drug Discovery Using LC-MS", American Society for Mass Spectrometry 1999 Conference Abstract, Dallas, TX, USA, 1999. 

Leclercq, L. L., Delatour, C., Marlot, E., Brunelle, F., McCullagh, M., Castro-Perez, J., Harland, G., and Preece, S. (2004), A new concept for fully automated metabolite identification by LC/MS. In Proceedings of the 52nd ASMS Conference on Mass Spectrometry and Allied Topics, Nashville, TN. 

In vitro drug screening Metabolic stability Membrane permeability Drug-drug interaction Automated metabolite identification Ackerman et al., 1998 Caldwell et al., 1998 Bu et al., 2000 Ayrton et al., 1998a Lopez et al., 1998... 

The rapid structure identification of metabolites is a powerful complement to previously described quantitative approaches. The utility of an automated metabolite identification approach, using LC/MS/MS with an ion trap mass spectrometer has been demon-strated.f In this study, MS" analysis is automated to provide maximum structural information in combination with predictive strategies for biotransformation. Automated data-dependent scan functions are used to generate full scan, MS/MS, and MS" mass spectra of... 

R. Ramanathan, D.L. McKenzie, M. Tugnait, K. Siebenaler, Application of semi-automated metabolite identification software in the drug discovery process for rapid identification of metabolites and the cytochrome P450 enzymes responsible for theirformation, J. Pharm. Biomed. Anal., 28 (2002) 945. 

A QTRAP instrument provides a wide range of options and greater power for metabolite identification. One aspect, which can often be a struggle, is the ability to automate much of this analysis for increased throughput, especially as metabolite identification is moved to earlier stages of the dmg discovery process. Recent work... 

Rourick, R. A., Jenkins, K. M., Walsh, J. P., Xu, R., Cai, Z., and Kassel, D. B. (2002). Integration of custom LC/MS automated data processing strategies for the rapid assessment of metabolic stability and metabolite identification in drug discovery. In Proceedings of the 50th ASMS Conference on Mass Spectrometry and Allied Topics, Orlando, FL. 

Isotopic cluster analysis can be built into the automated processing method and is used to target potential metabolites with the desired isotope ratios (Kind and Fiehn, 2006). For example, chlorine or bromine or radiolabeled drugs/metabolites can be pinpointed, at low levels, within a complex matrix background to dramatically enhance specificity and increase confidence in metabolite identification (Jindal and Lutz, 1986 Shirley et al., 1997). 

Arora, V. K., Li, Y., Philip, T., Yeola, S., and Mayol, R. F. (2001). Automated high-throughput metabolite identification using quadrupole time-of-flight (QTOF 2) mass spectrometer. In Proceeding of the 49th ASMS Conference on Mass Spectrometry and Allied Topics, Chicago, IL. 

Automated, rapid, high-throughput global analysis with minimal sample preparation, used for sample classification Limited ability for metabolite identification and quantification except for NMR... 

Efforts focused on the automated analysis of 2D NMR spectra of complex metabolite mixtures are still somewhat limited. Considering the importance of peak alignment in 2D spectra, a statistical method was developed to align NMR peaks from the same metabolites across multiple 2D NMR spectra (120). A semiautomated method for metabolite identification from 2D TOCSY and HSQC spectra was also developed (103). The software tool, MetaboMiner, makes use of a spectral reference library extracted from publicly available databases to automatically match peaks and identify compounds. 

King, R.C. Automated Product Ion Interpretation for Metabolite Identification, in Proceedings of the 49th ASMS Conference on Mass Spectrometry and Allied Topics, Chicago, IL, May 27-31. 

This LC-MS-based methodology can be automated to fit specialized needs within drug discovery based on throughput [62], The recent application of mass defect filtering [90] and high-resolution accurate mass analysis [33] provides further automated protocols for metabolite identification (see Chapters 5 and 6 for more on this topic). 

Bramwell, C., Wingate, J., and Elicone, C., GSH conjugate metabolite identification with a hybrid triple-quadrapole-linear ion-trap instrument and automated software-driven method development, Curr. Trends Mass Spectrom., May, 42, 2008. 

Overall, the use of a Q-TRAP Instrument with IDA demonstrated powerful capabilities of high throughput quality data acquisition. APEX metabolite identification examines the isotope patterns of the targeted ions to give more accurate results, increasing the confidence level of the automation. Meteor showed satisfactory prediction abilities that could be improved with more knowledge about more complicated or combined biotransformation pathways. In fact, in Meteor (version 12, the current version), version, M3 is predicted, albeit via the reverse mechanism to the one proposed i.e. aromatic ring... 

Nanospray ionization is a variation of regular ESI in that the typical flow rate is reduced to between 30 and 200 nL/min. Because of the very low flow rate at which samples are consumed, this technique is rapidly being integrated in many analytical applications including proteomics, metabolite characterization, and pharmaceutical analysis. An approach of combining fraction collection with automated chip-based NSI MS was recently introduced for metabolite identification (Hop, 2006 Staack et al., 2005). LC effluent was collected into a 96-well plate and the fraetions of interest were infused using an automated chip-based nanospray system for structure elucidation. 

M. Rojas-Cherto, J. Peironcely, P. Kasper, J. van der Hooft, R. H. de Vos, R. Vreeken, T. Hankemeier, and T. Reijmers. Metabolite identification using automated comparison of high-resolution multistage mass spectral trees. Ana/. Chem., 84(13) 5524-5534,2012. 

Figure 5.40 Product-ion spectrum of the (M + H)+ ion (m/z 614) of Indinavir with the proposed origins of the ions observed. Reprinted by permission of Elsevier Science from Identification of in vitro metabolites of Indinavir by Intelligent Automated LC-MS/MS (INTAMS) utilizing triple-quadrupole tandem mass spectrometry , by Yu, X., Cui, D. and Davis, M. R., Journal of the American Society for Mass Spectrometry, Vol. 10, pp. 175-183, Copyright 1999 by the American Society for Mass Spectrometry.

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