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  Critical Evaluation of Native Electrospray Ionization Mass Spectrometry for Fragment-Based Screening

Göth, M., Badock, V., Weiske, J., Pagel, K., & Kuropka, B. (2017). Critical Evaluation of Native Electrospray Ionization Mass Spectrometry for Fragment-Based Screening. ChemMedChem. doi:10.1002/cmdc.201700177.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-98FA-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-9C28-7
Genre: Journal Article

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 Creators:
Göth, Melanie1, 2, Author              
Badock, Volker3, Author
Weiske, Jörg3, Author
Pagel, Kevin1, 2, Author              
Kuropka, Benno3, 4, Author
Affiliations:
1Institute of Chemistry and Biochemistry Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany, escidoc:persistent22              
2Molecular Physics, Fritz Haber Institute, Max Planck Society, escidoc:634545              
3Protein Technologies, Lead Discovery Berlin Bayer AG , Müllerstraße 178, 13353 Berlin, Germany, escidoc:persistent22              
4Institute of Chemistry and Biochemistry Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany, escidoc:persistent22              

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Free keywords: native mass spectrometry; fragment-based screening; protein-ligand complex
 Abstract: Fragment-based screening presents a promising alternative to high-throughput screening and has gained great attention over the last years. So far, only a few studies discuss mass spectrometry as a screening technology for fragments. Here, we applied native electrospray ionization mass spectrometry (ESI-MS) for screening defined sets of fragments against four different target proteins. Fragments were selected from a primary screen conducted by thermal shift assay (TSA) and represent different binding categories. Our data show that beside specific complex formation, many fragments show extensive multiple binding as well as charge-state shifts. Both of these factors complicate automated data analysis and lower the attractiveness of native MS as a primary screening tool for fragments. A comparison of hits identified by native MS and TSA shows good agreement for two proteins. Furthermore, we discuss general obstacles including the determination of an optimal fragment concentration and the question of how to rank fragment hits according to their affinity. In conclusion, we consider native MS a highly valuable tool for the validation and deeper investigation of promising fragment hits rather than a method for primary screening.

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Language(s): eng - English
 Dates: 2017-03-212017-06-122017-06-15
 Publication Status: Published online
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1002/cmdc.201700177
 Degree: -

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Title: ChemMedChem
  Other : ChemMedChem
Source Genre: Journal
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Publ. Info: Weinheim, Germany : Wiley-VCH
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 1860-7179
CoNE: http://pubman.mpdl.mpg.de/cone/journals/resource/954925399508