Identification of small molecules using accurate mass MS/MS search

Abstract

Tandem mass spectral library search (MS/MS) is the fastest way to correctly annotate MS/MS spectra from screening small molecules in fields such as environmental analysis, drug screening, lipid analysis, and metabolomics. The confidence in MS/MS-based annotation of chemical structures is impacted by instrumental settings and requirements, data acquisition modes including data-dependent and data-independent methods, library scoring algorithms, as well as post-curation steps. We critically discuss parameters that influence search results, such as mass accuracy, precursor ion isolation width, intensity thresholds, centroiding algorithms, and acquisition speed. A range of publicly and commercially available MS/MS databases such as NIST, MassBank, MoNA, LipidBlast, Wiley MSforID, and METLIN are surveyed. In addition, software tools including NIST MS Search, MS-DIAL, Mass Frontier, SmileMS, Mass++, and XCMS to perform fast MS/MS search are discussed. MS/MS scoring algorithms and challenges during compound annotation are reviewed. Advanced methods such as the in silico generation of tandem mass spectra using quantum chemistry and machine learning methods are covered. Community efforts for curation and sharing of tandem mass spectra that will allow for faster distribution of scientific discoveries are discussed.

Challenges and emergent solutions for LC‐MS/MS based untargeted metabolomics in diseases

“…In summary, advancement in MS instrumentations and the development of innovative structure elucidation strategies to enrich metabolite identifications allows for in‐depth mass‐spectrometry based metabolomics analysis . There might be a host of other paradigm shifts to improve metabolome identification, some waiting to be crystalized .…”

High‐resolution gas chromatography/mass spectrometry metabolomics of non‐human primate serum

“…Gas chromatography, amenable to polar primary metabolitesand fatty acids, provides advantages over other chromatographic systems by virtue of its excellent chromatographic resolution, and it can be used effectively for routine quantitative metabolomic applications. With the advent of modern instruments, such as Orbitrap technology based mass spectrometers, that are capable of sub‐ppm mass accuracy at high mass resolutions (i.e., >50,000), calculation of predicted molecular formulae based on the mass defect of a detected ion is now possible . Orbitrap‐based high‐resolution (HR) accurate mass instrumentation offers the ability to obtain mass spectral data at high resolving power with mass accuracies <1 ppm.…”

METLIN: A Technology Platform for Identifying Knowns and Unknowns

“…These data complement the data from other databases, which have been collected for electron impact (EI) or nuclear magnetic resonance (NMR) instrumentation. 3–5 Recently, to improve the coverage of metabolites and aid with its annotation, in silico MS/MS spectra have now been generated on METLIN’s additional molecules (that currently have no experimental data). These data are based on advanced machine learning algorithms, 6–8 the growing METLIN database, and the unique fragmentation information provided by stable isotopes.…”