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Chemical informatics and target identification in a zebrafish phenotypic screen


Target identification is a core challenge in chemical genetics. Here we use chemical similarity to computationally predict the targets of 586 compounds that were active in a zebrafish behavioral assay. Among 20 predictions tested, 11 compounds had activities ranging from 1 nM to 10,000 nM on the predicted targets. The roles of two of these targets were tested in the original zebrafish phenotype. Prediction of targets from chemotype is rapid and may be generally applicable.

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Figure 1: Compounds for which at least one target is predicted.
Figure 2: Testing target relevance by phenocopy and functional competition.


  1. Harding, M.W., Galat, A., Uehling, D.E. & Schreiber, S.L. Nature 341, 758–760 (1989).

    Article  CAS  Google Scholar 

  2. Leung, D., Hardouin, C., Boger, D.L. & Cravatt, B.F. Nat. Biotechnol. 21, 687–691 (2003).

    Article  CAS  Google Scholar 

  3. Ong, S.E. et al. Proc. Natl. Acad. Sci. USA 106, 4617–4622 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Haggarty, S.J. et al. Chem. Biol. 7, 275–286 (2000).

    Article  CAS  Google Scholar 

  6. Schreiber, S.L. Nat. Chem. Biol. 1, 64–66 (2005).

    Article  CAS  Google Scholar 

  7. Seiler, K.P. et al. Nucleic Acids Res. 36, D351–D359 (2008).

    Article  CAS  Google Scholar 

  8. Palchaudhuri, R. & Hergenrother, P.J. ACS Chem. Biol. 6, 21–33 (2011).

    Article  CAS  Google Scholar 

  9. Lamb, J. et al. Science 313, 1929–1935 (2006).

    Article  CAS  Google Scholar 

  10. Keiser, M.J., Irwin, J.J. & Shoichet, B.K. Biochemistry 49, 10267–10276 (2010).

    Article  CAS  Google Scholar 

  11. Paolini, G.V., Shapland, R.H., van Hoorn, W.P., Mason, J.S. & Hopkins, A.L. Nat. Biotechnol. 24, 805–815 (2006).

    Article  CAS  Google Scholar 

  12. Yildirim, M.A., Goh, K.I., Cusick, M.E., Barabasi, A.L. & Vidal, M. Nat. Biotechnol. 25, 1119–1126 (2007).

    Article  CAS  Google Scholar 

  13. Keiser, M.J. et al. Nat. Biotechnol. 25, 197–206 (2007).

    Article  CAS  Google Scholar 

  14. Keiser, M.J. et al. Nature 462, 175–181 (2009).

    Article  CAS  Google Scholar 

  15. Kokel, D. et al. Nat. Chem. Biol. 6, 231–237 (2010).

    Article  CAS  Google Scholar 

  16. Hert, J., Keiser, M.J., Irwin, J.J., Oprea, T.I. & Shoichet, B.K. J. Chem. Inf. Model. 48, 755–765 (2008).

    Article  CAS  Google Scholar 

  17. Rogers, D. & Hahn, M. J. Chem. Inf. Model. 50, 742–754 (2010).

    Article  CAS  Google Scholar 

  18. James, C., Weininger, D. & Delany, J. Daylight Theory Manual (Daylight Chemical Information Systems Inc., 2011).

  19. Willett, P., Barnard, J.M. & Downs, G.M. J. Chem. Inf. Comput. Sci. 38, 983–996 (1998).

    Article  CAS  Google Scholar 

  20. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

  21. Young, D.W. et al. Nat. Chem. Biol. 4, 59–68 (2008).

    Article  CAS  Google Scholar 

  22. Mestres, J., Gregori-Puigjane, E., Valverde, S. & Sole, R.V. Mol. Biosyst. 5, 1051–1057 (2009).

    Article  CAS  Google Scholar 

  23. Alderton, W., Davenport, R. & Fish, P.V. Drugs Future 35, 517–521 (2010).

    Article  CAS  Google Scholar 

  24. Kinnings, S.L. et al. PLOS Comput. Biol. 5, e1000423 (2009).

    Article  Google Scholar 

  25. Hert, J., Irwin, J.J., Laggner, C., Keiser, M.J. & Shoichet, B.K. Nat. Chem. Biol. 5, 479–483 (2009).

    Article  CAS  Google Scholar 

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We thank S. Morris for help with Cytoscape. This work was supported by US National Institutes of Health grants GM71896 (to J.J.I. and B.K.S.), AG02132 (to S. Prusiner and B.K.S.), MH085205 and MH086867 (to R.P.), MH091449 (to D.K.), R01 MH093603 and R01 NS49272 (to D.L.M.); a Rogers Family Foundation award (to M.J.K.); the National Institutes of Mental Health Psychoactive Drug Screening Program, grant U19MH82441; the Michael Hooker Chair (to B.L.R.); and fellowships from the Max Kade Foundation (to C.L.) and the European Molecular Biology Organization (to A.T.).

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Authors and Affiliations



The strategy was devised by B.K.S. and R.T.P., the PMR assay by D.K., and target predictions and other calculations by C.L., with assistance and editing by J.J.I., M.J.K., H.L. and B.K.S. Electrophysiology was designed by D.L.M. and implemented by A.T., and GPCR and kinase experiments were designed and implemented by B.L.R. and V.S., who also advised on target-phenotype associations. Zebrafish pharmacology was conducted by D.K. with assistance by C.Y.J.C.

Corresponding authors

Correspondence to Bryan L Roth, Randall T Peterson or Brian K Shoichet.

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The authors declare no competing financial interests.

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Laggner, C., Kokel, D., Setola, V. et al. Chemical informatics and target identification in a zebrafish phenotypic screen. Nat Chem Biol 8, 144–146 (2012).

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