The emerging role of mass spectrometry-based proteomics in drug discovery

doi:10.1038/s41573-022-00409-3

Review

. 2022 Sep;21(9):637-654.

doi: 10.1038/s41573-022-00409-3. Epub 2022 Mar 29.

The emerging role of mass spectrometry-based proteomics in drug discovery

Felix Meissner^{1

2}, Jennifer Geddes-McAlister^{3

4

5}, Matthias Mann^{5

6}, Marcus Bantscheff⁷

Affiliations

¹ Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany. felix.meissner@uni-bonn.de.
² Systems Immunology and Proteomics, Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany. felix.meissner@uni-bonn.de.
³ Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany.
⁴ Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
⁵ Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.
⁶ Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Cellzome GmbH, Heidelberg, Germany. marcus.x.bantscheff@gsk.com.

PMID: 35351998
DOI: 10.1038/s41573-022-00409-3

Review

The emerging role of mass spectrometry-based proteomics in drug discovery

Felix Meissner et al. Nat Rev Drug Discov. 2022 Sep.

. 2022 Sep;21(9):637-654.

doi: 10.1038/s41573-022-00409-3. Epub 2022 Mar 29.

Authors

Felix Meissner^{1

2}, Jennifer Geddes-McAlister^{3

4

5}, Matthias Mann^{5

6}, Marcus Bantscheff⁷

Affiliations

¹ Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany. felix.meissner@uni-bonn.de.
² Systems Immunology and Proteomics, Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany. felix.meissner@uni-bonn.de.
³ Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany.
⁴ Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
⁵ Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.
⁶ Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Cellzome GmbH, Heidelberg, Germany. marcus.x.bantscheff@gsk.com.

PMID: 35351998
DOI: 10.1038/s41573-022-00409-3

Abstract

Proteins are the main targets of most drugs; however, system-wide methods to monitor protein activity and function are still underused in drug discovery. Novel biochemical approaches, in combination with recent developments in mass spectrometry-based proteomics instrumentation and data analysis pipelines, have now enabled the dissection of disease phenotypes and their modulation by bioactive molecules at unprecedented resolution and dimensionality. In this Review, we describe proteomics and chemoproteomics approaches for target identification and validation, as well as for identification of safety hazards. We discuss innovative strategies in early-stage drug discovery in which proteomics approaches generate unique insights, such as targeted protein degradation and the use of reactive fragments, and provide guidance for experimental strategies crucial for success.

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References

1. Hughes, J. P., Rees, S., Kalindjian, S. B. & Philpott, K. L. Principles of early drug discovery. Br. J. Pharmacol. 162, 1239–1249 (2011). - PubMed - PMC - DOI
1. Swinney, D. C. & Anthony, J. How were new medicines discovered? Nat. Rev. Drug Discov. 10, 507–519 (2011). This Review provides an excellent analysis of discovery strategies and molecular mode of action of approved drugs. - PubMed - DOI
1. Clark, M. A. et al. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat. Chem. Biol. 5, 647–654 (2009). - PubMed - DOI
1. Renaud, J. P. et al. Biophysics in drug discovery: impact, challenges and opportunities. Nat. Rev. Drug Discov. 15, 679–698 (2016). - PubMed - DOI
1. Wang, T., Wei, J. J., Sabatini, D. M. & Lander, E. S. Genetic screens in human cells using the CRISPR-Cas9 system. Science 343, 80–84 (2014). - PubMed - DOI

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[1] Hughes, J. P., Rees, S., Kalindjian, S. B. & Philpott, K. L. Principles of early drug discovery. Br. J. Pharmacol. 162, 1239–1249 (2011). - PubMed - PMC - DOI

[2] Hughes, J. P., Rees, S., Kalindjian, S. B. & Philpott, K. L. Principles of early drug discovery. Br. J. Pharmacol. 162, 1239–1249 (2011). - PubMed - PMC - DOI

[3] Swinney, D. C. & Anthony, J. How were new medicines discovered? Nat. Rev. Drug Discov. 10, 507–519 (2011). This Review provides an excellent analysis of discovery strategies and molecular mode of action of approved drugs. - PubMed - DOI

[4] Swinney, D. C. & Anthony, J. How were new medicines discovered? Nat. Rev. Drug Discov. 10, 507–519 (2011). This Review provides an excellent analysis of discovery strategies and molecular mode of action of approved drugs. - PubMed - DOI

[5] Clark, M. A. et al. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat. Chem. Biol. 5, 647–654 (2009). - PubMed - DOI

[6] Clark, M. A. et al. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat. Chem. Biol. 5, 647–654 (2009). - PubMed - DOI

[7] Renaud, J. P. et al. Biophysics in drug discovery: impact, challenges and opportunities. Nat. Rev. Drug Discov. 15, 679–698 (2016). - PubMed - DOI

[8] Renaud, J. P. et al. Biophysics in drug discovery: impact, challenges and opportunities. Nat. Rev. Drug Discov. 15, 679–698 (2016). - PubMed - DOI

[9] Wang, T., Wei, J. J., Sabatini, D. M. & Lander, E. S. Genetic screens in human cells using the CRISPR-Cas9 system. Science 343, 80–84 (2014). - PubMed - DOI

[10] Wang, T., Wei, J. J., Sabatini, D. M. & Lander, E. S. Genetic screens in human cells using the CRISPR-Cas9 system. Science 343, 80–84 (2014). - PubMed - DOI

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The emerging role of mass spectrometry-based proteomics in drug discovery

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The emerging role of mass spectrometry-based proteomics in drug discovery

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