Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

Authors

  • Dr. Slava Ziegler,

    Corresponding author
    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
    • Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    Search for more papers by this author
  • Dr. Verena Pries,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
    Search for more papers by this author
  • Dr. Christian Hedberg,

    Corresponding author
    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
    • Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    Search for more papers by this author
  • Prof. Dr. Herbert Waldmann

    Corresponding author
    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
    • Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    Search for more papers by this author

Abstract

Identification and confirmation of bioactive small-molecule targets is a crucial, often decisive step both in academic and pharmaceutical research. Through the development and availability of several new experimental techniques, target identification is, in principle, feasible, and the number of successful examples steadily grows. However, a generic methodology that can successfully be applied in the majority of the cases has not yet been established. Herein we summarize current methods for target identification of small molecules, primarily for a chemistry audience but also the biological community, for example, the chemist or biologist attempting to identify the target of a given bioactive compound. We describe the most frequently employed experimental approaches for target identification and provide several representative examples illustrating the state-of-the-art. Among the techniques currently available, protein affinity isolation using suitable small-molecule probes (pulldown) and subsequent mass spectrometric analysis of the isolated proteins appears to be most powerful and most frequently applied. To provide guidance for rapid entry into the field and based on our own experience we propose a typical workflow for target identification, which centers on the application of chemical proteomics as the key step to generate hypotheses for potential target proteins.

Ancillary