Large-scale chemoproteomics expedites ligand discovery and predicts ligand behavior in cells.

Journal: Science (New York, N.Y.)
PMID: 38662832

Abstract

Chemical modulation of proteins enables a mechanistic understanding of biology and represents the foundation of most therapeutics. However, despite decades of research, 80% of the human proteome lacks functional ligands. Chemical proteomics has advanced fragment-based ligand discovery toward cellular systems, but throughput limitations have stymied the scalable identification of fragment-protein interactions. We report proteome-wide maps of protein-binding propensity for 407 structurally diverse small-molecule fragments. We verified that identified interactions can be advanced to active chemical probes of E3 ubiquitin ligases, transporters, and kinases. Integrating machine learning binary classifiers further enabled interpretable predictions of fragment behavior in cells. The resulting resource of fragment-protein interactions and predictive models will help to elucidate principles of molecular recognition and expedite ligand discovery efforts for hitherto undrugged proteins.

Authors

  • Fabian Offensperger
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Gary Tin
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Miquel Duran-Frigola
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Elisa Hahn
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Sarah Dobner
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Christopher W Am Ende
    Medicine Design, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
  • Joseph W Strohbach
    Medicine Design, Pfizer, Cambridge, MA 02139, USA.
  • Andrea Rukavina
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Vincenth Brennsteiner
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Kevin Ogilvie
    Medicine Design, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
  • Nara Marella
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Katharina Kladnik
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Rodolfo Ciuffa
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Jaimeen D Majmudar
    Pfizer Research & Development, Cambridge, Massachusetts 02139, United States.
  • S Denise Field
    Medicine Design, Pfizer, Cambridge, MA 02139, USA.
  • Ariel Bensimon
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Luca Ferrari
    Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna Biocenter 5, 1030 Vienna, Austria.
  • Evandro Ferrada
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Amanda Ng
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Zhechun Zhang
    Molecular Informatics, Machine Learning and Computational Sciences, Early Clinical Development, Pfizer, Cambridge, MA 02139, USA.
  • Gianluca Degliesposti
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Andras Boeszoermenyi
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Sascha Martens
    Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna Biocenter 5, 1030 Vienna, Austria.
  • Robert Stanton
    Molecular Informatics, Machine Learning and Computational Sciences, Early Clinical Development, Pfizer, Cambridge, MA 02139, USA.
  • André C Müller
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • J Thomas Hannich
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • David Hepworth
    Medicine Design, Pfizer, Cambridge, MA 02139, USA.
  • Giulio Superti-Furga
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Stefan Kubicek
    CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
  • Monica Schenone
    Medicine Design, Pfizer, Cambridge, MA 02139, USA.
  • Georg E Winter
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.

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