An open workflow to generate "MS-Ready" structures and improve non-targeted mass spectrometry
High-throughput non-targeted analyses (NTA) rely on chemical reference databases for tentative identification of observed chemical features. Many of these databases and online resources incorporate chemical structure data not in a form that is readily observed by mass spectrometry (e.g., structures that may contain salts, solvates, chemicals with stereochemistry included). Our center has previously reported on the production of “QSAR-ready structures”, forms of chemical structures processed for use in prediction models that are de-salted, de-solvated, and containing no stereochemistry information. While appropriate for property prediction and modeling purposes, QSAR-ready structures do not completely address structural issues of relevance to mass spectrometry. In this work we have adapted the workflow used to generate QSAR-ready structures to allow for the creation of “MS-Ready structures” that includes procedures to separate mixtures and multi-component substances within our database. The goal of this research is to provide an open workflow such that all users and architects of chemical reference databases have the capability to generate and query structures as observed in a mass spectrometer. Chemical structures were processed using KNIME Analytics Platform® and incorporated into the US EPA’s CompTox Chemistry Dashboard so that tentative identification is achievable by querying MS-Ready structures by monoisotopic mass and molecular formula. Inclusion of MS-Ready structures within the Dashboard improved the coverage of candidate structures observed via HRMS, indicating the increased potential for identification of unknowns. The availability of pre-processed MS-ready structure files as Open Data and the developing services for direct integration with other software tools positions the Dashboard as a valuable resource for the mass spectrometry community. This abstract does not necessarily represent the views or policies of the U.S. Environmental Protection Agency.
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An open workflow to generate "MS-Ready" structures and improve non-targeted mass spectrometry
- 1. Photo image area measures 2” H x 6.93” W and can be masked by a collage strip of one, two or three images. The photo image area is located 3.19” from left and 3.81” from top of page. Each image used in collage should be reduced or cropped to a maximum of 2” high, stroked with a 1.5 pt white frame and positioned edge-to-edge with accompanying images. An open workflow to generate “MS Ready” structures and improve non-targeted mass spectrometry Office of Research and Development National Center for Computational Toxicology, RTP, NC August 24, 2017 Andrew D. McEachran, Kamel Mansouri, Chris Grulke, Antony J. Williams http://orcid.org/0000-0003-1423-330X The views expressed in this presentation are those of the author and do not necessarily reflect the views or policies of the U.S. EPA ANYL 435
- 2. Comparing Analysis Approaches • Targeted Analysis: - We know exactly what we’re looking for - 10s – 100s of chemicals • Suspect Screening Analysis (SSA): - We have chemicals of interest - 100s – 1,000s of chemicals • Non-Targeted Analysis (NTA): - We have no preconceived lists - 1,000s – 10,000s of chemicals - In dust, soil, food, air, water, products- potential exposure source for plants, animals, and humans Slide from Sobus, Williams 8/24/2017
- 3. General Goals of SSA/NTA - 1 Dust Sample - Negative Ionization Mode - 300 Extracted “Molecular Features” 1) Prioritize “Molecular Features” 2) Correctly assign formulas 3) Correctly assign structures 4) Identify chemical sources 5) Predict chemical concentrations C17H19NO3 12 µg/g (1) (2) (3) (4) (5) EXPOSURE 8/24/2017
- 4. 8/24/2017 Analytical Instruments Comp. Tools & Workflows Databases The General Approach
- 5. Data Source Ranking of “known unknowns” • Mass and/or formula unknown to a researcher, contained within a reference database • Most likely candidate chemicals have the most references/sources 8/24/2017 C14H22N2O3 266.16304 Chemical Reference Database Sorted candidate structures
- 6. Identifying structures via High-Resolution Mass Spectrometry? 8/24/2017
- 8. MS-Ready Structure Processing 1. Removal of inorganics and separation of mixtures 2. Removal of salts and counterions 3. Conversion of tautomers to consistent representations 4. Neutralization of charged structures and removal of stereochemistry information 5. Addition of explicit hydrogen atoms and aromatization of structures 6. Removal of duplicates 8/24/2017
- 14. PFOS 8/24/2017
- 15. PFOS 8/24/2017 -All of these forms of PFOS returned with a single formula search -Requires multiple searches in ChemSpider, PubChem, etc.
- 16. ENTACT Trial • Collaborative trial with >20 lab participants • Blinded mixtures, environmental samples, etc. • Identify what you can using what you have 8/24/2017
- 17. 8/24/2017 Methapyrilene fumarate Formula: C40H50N6O12S2 Raloxifene hydrochloride Formula: C28H28ClNO4S MS-Ready: C28H27NO4S MS-Ready: C14H19N3S C4H4O4
- 18. 8/24/2017 Schymanski and Williams. 2017. DOI: 10.1021/acs.est.7b01908
- 19. MS-Ready Structures in NTA 8/24/2017 -Data source ranking of MS-Ready Structures
- 22. 8/24/2017
- 23. Conclusions • Database searching is a critical part of NTA/SSA workflows • Providing accurate mappings between the MS-Ready form and all forms of a chemical contained within a database improves identification • EPA’s CompTox Chemistry Dashboard provides MS- Ready structures for search and download 8/24/2017
- 24. Acknowledgements EPA NCCT Tony Williams Chris Grulke John Wambaugh Kamel Mansouri* Jeff Edwards Ann Richard Jennifer Smith EPA NERL Katherine Phillips Kristin Isaacs Kathie Dionisio Jon Sobus Mark Strynar Elin Ulrich Seth Newton Jarod Grossman Sarah Laughlin- Toth* Aurelie Marcotte* *ORISE Research Participant 8/24/2017
- 25. Questions? • mceachran.andrew@epa.gov • http://orcid.org/0000-0003-1423-330X • Associated presentations: –8/22: ENVR 206- S. Newton –8/23: ANYL 348- S. Laughlin-Toth –8/23: CINF 121- A. Williams –8/24: ENVR 548- J. Sobus 8/24/2017