Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Commentary
  • Published:

Challenges facing the biologist doing chemical genetics

The goal of high-throughput screening (HTS) from the perspective of the biologist is to identify a highly specific small molecule that can be used to inhibit a protein in its normal biological context. Although several useful small molecules have been identified with HTS, there are many challenges to be considered when contemplating a screen, especially by those unfamiliar with chemical biology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Comparison of a traditional high-throughput screen with a screen that selects for and enriches potential lead compounds.

References

  1. Hung, D.T., Jamison, T.F. & Schreiber, S.L. Chem. Biol. 3, 623–639 (1996).

    Article  CAS  Google Scholar 

  2. Crews, C.M. & Shotwell, J.B. Prog. Cell Cycle Res. 5, 125–133 (2003).

    Google Scholar 

  3. Tamura, G., Ando, K., Suzuki, S., Takatsuki, A. & Arima, K. J. Antibiot. (Tokyo) 21, 160–161 (1968).

    Article  CAS  Google Scholar 

  4. Horakova, K. & Betina, V. Neoplasma 24, 21–27 (1977).

    CAS  Google Scholar 

  5. Betina, V. & Micekova, D. Z. Allg. Mikrobiol. 12, 355–364 (1972).

    Article  CAS  Google Scholar 

  6. Wani, M.C., Taylor, H.L., Wall, M.E., Coggon, P. & McPhail, A.T. J. Am. Chem. Soc. 93, 2325–2327 (1971).

    Article  CAS  Google Scholar 

  7. Zhang, J.H., Chung, T.D. & Oldenburg, K.R. J. Biomol. Screen. 4, 67–73 (1999).

    Article  CAS  Google Scholar 

  8. Mitchison, T.J. Chembiochem. 6, 33–39 (2005).

    Article  CAS  Google Scholar 

  9. Wignall, S.M. et al. Chem. Biol. 11, 135–146 (2004).

    Article  CAS  Google Scholar 

  10. Luesch, H. et al. Chem. Biol. 12, 55–63 (2005).

    Article  CAS  Google Scholar 

  11. Mayer, T.U. et al. Science 286, 971–974 (1999).

    Article  CAS  Google Scholar 

  12. Yarrow, J.C., Totsukawa, G., Charras, G.T. & Mitchison, T.J. Chem. Biol. 12, 385–395 (2005).

    Article  CAS  Google Scholar 

  13. Schneider, G. & Fechner, U. Nat. Rev. Drug Discov. 4, 649–663 (2005).

    Article  CAS  Google Scholar 

  14. Gadek, T.R. & Nicholas, J.B. Biochem. Pharmacol. 65, 1–8 (2003).

    Article  CAS  Google Scholar 

  15. Chang, Y.T. et al. Chem. Biol. 6, 361–375 (1999).

    Article  CAS  Google Scholar 

  16. Halpin, D.R. & Harbury, P.B. PLoS Biol. 2, E174 (2004).

    Article  Google Scholar 

  17. Gartner, Z.J. et al. Science 305, 1601–1605 (2004).

    Article  CAS  Google Scholar 

  18. Erlanson, D.A., Wells, J.A. & Braisted, A.C. Annu. Rev. Biophys. Biomol. Struct. 33, 199–223 (2004).

    Article  CAS  Google Scholar 

  19. Cousins, G.R., Poulsen, S.A. & Sanders, J.K. Curr. Opin. Chem. Biol. 4, 270–279 (2000).

    Article  CAS  Google Scholar 

  20. Lam, R.T. et al. Science 308, 667–669 (2005).

    Article  CAS  Google Scholar 

  21. Becattini, B. & Pellecchia, M. Chemistry (2005).

  22. Kitchen, D.B., Decornez, H., Furr, J.R. & Bajorath, J. Nat. Rev. Drug Discov. 3, 935–949 (2004).

    Article  CAS  Google Scholar 

  23. Kuntz, I.D. Science 257, 1078–1082 (1992).

    Article  CAS  Google Scholar 

  24. Jain, A.N. J. Med. Chem. 46, 499–511 (2003).

    Article  CAS  Google Scholar 

  25. Irwin, J.J. & Shoichet, B.K. J. Chem. Inf. Model. 45, 177–182 (2005).

    Article  CAS  Google Scholar 

  26. McGovern, S.L., Helfand, B.T., Feng, B. & Shoichet, B.K. J. Med. Chem. 46, 4265–4272 (2003).

    Article  CAS  Google Scholar 

  27. Feng, B., Shelat, A., Thompson, N.D., Guy, R.K. & Shoichet, B.K. Nat. Chem. Biol. 1, 146–148 (2005).

    Article  CAS  Google Scholar 

  28. Turek-Etienne, T.C. et al. J. Biomol. Screen. 8, 176–184 (2003).

    Article  CAS  Google Scholar 

  29. Banks, P., Gosselin, M. & Prystay, L. J. Biomol. Screen. 5, 329–334 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank D. Halpin and J. Williams for useful discussions.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Soderholm, J., Uehara-Bingen, M., Weis, K. et al. Challenges facing the biologist doing chemical genetics. Nat Chem Biol 2, 55–58 (2006). https://doi.org/10.1038/nchembio0206-55

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio0206-55

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing