Small molecule discovery from LC-MS data with metaboseek Maximilian J. Helf 1,2 , Bennett W. Fox 1 and Frank C. Schroeder 1 1 Boyce Thompson Institute, Cornell University, USA, 2 Novartis Institutes of BioMedical Research, Basel, Switzerland Comparative analysis of high resolution mass spectrometry (HRMS) data is a powerful approach to identify products and intermediates of biosynthetic pathways, and more generally, enables linking genotypes and phenotypes with associated metabotypes. However, data processing is presenting a productivity bottleneck, potentially leading to missed discovery opportunities. To facilitate the identification of biologically relevant small molecules, we recently introduced Metaboseek 1 , an R/shiny-based, discovery-oriented platform to extract differential features from HPLC-HRMS data in a user- friendly graphical user interface. It includes functionality to rapidly inspect feature-specific data, find groups of structurally related compounds and assist compound identification and dereplication. In addition to offering a convenient interface to run the popular xcms package for MS data processing and feature detection, Metaboseek also handles statistical analysis, prediction of molecular formulas, annotation of MS2 spectra, MS2 molecular networking and chemical compound database searches. By making a range of metabolomics tools more accessible inside a single user interface, Metaboseek enables high-throughput identification of differential molecular features and facilitates structure elucidation of novel compounds, addressing an urgent need to explore the vast universe of unknown compounds revealed by HPLC- HRMS 2,3 . For tool developers, the individual modules of Metaboseek provide building blocks that can be combined into specialized data analysis apps with minimal effort, making it significantly easier to build a graphical user interface for metabolomics software. As an example, we built a new tool for the annotation of MS2 spectra from modified peptide natural products that aids assignment of sites of post-translational modifications. Metaboseek provides a flexible and expandable platform to facilitate the comprehensive annotation of metabolomes, including elucidation of the structures and associated biosynthetic networks of the vast numbers of yet unidentified biogenic small molecules. The software is available for download and as an online preview version at https://metaboseek.com. References 1. M. J. Helf, B. W. Fox, A. B. Artyukhin, Y. K. Zhang and F. C. Schroeder, Nat. Commun. , 2022, 13 , 1–11. 2. C. J. J. Wrobel, J. Yu, P. R. Rodrigues, A. H. Ludewig, B. J. Curtis, S. M. Cohen, B. W. Fox, M. P. O’Donnell, P. W. Sternberg and F. C. Schroeder, J. Am. Chem. Soc. , 2021, 143 , 14676–14683. 3. H. H. Le, C. J. J. Wrobel, S. M. Cohen, J. Yu, H. Park, M. J. Helf, B. J. Curtis, J. C. Kruempel, P. R. Rodrigues, P. J. Hu, P. W. Sternberg and F. C. Schroeder, Elife , 2020, 9 , 1–42.
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