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.

How many drug targets are there?

Abstract

For the past decade, the number of molecular targets for approved drugs has been debated. Here, we reconcile apparently contradictory previous reports into a comprehensive survey, and propose a consensus number of current drug targets for all classes of approved therapeutic drugs. One striking feature is the relatively constant historical rate of target innovation (the rate at which drugs against new targets are launched); however, the rate of developing drugs against new families is significantly lower. The recent approval of drugs that target protein kinases highlights two additional trends: an emerging realization of the importance of polypharmacology, and also the power of a gene-family-led approach in generating novel and important therapies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Gene-family distribution of current drugs per drug substance.
Figure 2: Frequency distribution for small-molecule drug potencies.
Figure 3: Rate of target innovation.

References

  1. 1

    Drews, J. Genomic sciences and the medicine of tomorrow. Nature Biotechnol. 14, 1516–1518 (1996).

    CAS  Article  Google Scholar 

  2. 2

    Drews, J. & Ryser, S. Classic drug targets. Nature Biotechnol. 15, 1318–1319 (1997).

    CAS  Article  Google Scholar 

  3. 3

    Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 23, 3–25 (1997).

    CAS  Article  Google Scholar 

  4. 4

    Hopkins, A. L. & Groom, C. R. The druggable genome. Nature Rev. Drug Discov. 1, 727–730 (2002).

    CAS  Article  Google Scholar 

  5. 5

    Golden, J. B. Prioritizing the human genome: knowledge management for drug discovery. Curr. Opin. Drug Discov. Dev. 6, 310–316 (2003).

    CAS  Google Scholar 

  6. 6

    Golden, J. Towards a tractable genome: knowledge management in drug discovery. Curr. Drug Discov. 17–20 (2003).

  7. 7

    Wishart, D. S. et al. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 43, D668–D672 (2006).

    Article  Google Scholar 

  8. 8

    Imming, P., Sinning, C. & Meyer, A. Drugs, their targets and the nature and number of drug targets. Nature Rev. Drug Discov. 5, 821–834 (2006).

    CAS  Article  Google Scholar 

  9. 9

    Zheng, C., Han, L., Yap, C. W., Xie, B. & Chen, Y. Progress and problems in the exploration of therapeutic targets. Drug Discov. Today 11, 412–420 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Zheng, C. J. et al. Therapeutic targets: progress of their explorations and investigation of their characteristics. Pharma. Rev. 58, 259–279 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 2, 561–566 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Fabian, M. A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nature Biotechnol. 23, 329–336 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Atwell, S. et al. A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase. J. Biol. Chem. 279, 55827–55832 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Heinrich, M. C. et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96, 925–932 (2000).

    CAS  Google Scholar 

  15. 15

    Ahmad, T. & Eisen, T. Kinase inhibition with BAY 43–9006 in renal cell carcinoma. Clin. Cancer Res. 10, 6388S–6392S (2004).

    CAS  Article  Google Scholar 

  16. 16

    Weber, A. et al. Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: New pharmacological opportunities due to related binding site recognition. J. Med. Chem. 47, 550–557 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Paolini, G. V., Shapland, R. H. B., van Hoorn, W. P., Mason, J. S. & Hopkins, A. L. Global mapping of pharmacological space. Nature Biotechnol. 24, 805–815 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Hopkins, A. L., Mason, J. S. & Overington, J. P. Can we rationally design promiscuous drugs?. Curr. Opin. Struct. Biol. 16, 127–136 (2006).

    CAS  Article  Google Scholar 

  19. 19

    Murzin, A. G., Brenner, S. E., Hubbard, T. & Chothia, C. SCOP: a structural classification of proteins database for the investigation of sequences and structures. J. Mol. Biol. 274, 536–540 (1995).

    Google Scholar 

  20. 20

    Bateman, A. et al. The Pfam Protein Families Database. Nucleic Acids Res. 32, D138–D141 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Koonin, E. V., Wolf, Y. I. & Karev, G. P. The structure of the protein universe and genome evolution. Nature 420, 218–223 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Vitkup, D., Melamud, E., Moult, J. & Sander, C. Completeness in structural genomics. Nature Struct. Biol. 8, 559–566 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Berman, H. M. et al. The Protein Data Bank. Nucleic Acid Res. 28, 235–242 (2000).

    CAS  Article  Google Scholar 

  24. 24

    McKusick, V. A. in Mendelian Inheritance in Man 12th Edn (John Hopkins University Press, Baltimore, 1998).

    Google Scholar 

  25. 25

    NIHCM 24 pp (National Institute for Health Care Management Research and Educational Foundation, 2002).

  26. 26

    Christensen, C. M. The Innovator's Dilemma: When New Technologies Cause Great Firms to Fail (Harvard Business School Press, Cambridge, 1997).

    Google Scholar 

  27. 27

    Raju, T. N. The Nobel chronicles. Lancet 355, 1022 (2000).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank I. Carruthers, R. Cox, S. Rehman and J. Stevenson for assistance with data curation and analysis.

Author information

Affiliations

Authors

Corresponding author

Correspondence to John P. Overington.

Ethics declarations

Competing interests

John Overington and Bissan Al-Lazikani are employees of Inpharmatica Ltd. Andrew Hopkins is an employee of Pfizer.

Related links

Related links

FURTHER INFORMATION

Poster on the molecular pharmacopoeia

Glossary

Cytochrome P450 3A4

This enzyme is arguably the most important enzyme for drug metabolism; it metabolizes more than 50% of marketed drugs, and is frequently involved in drug–drug interactions.

New molecular entity

A drug that contains an active ingredient that has not been previously approved by the US FDA.

Pharmacophore

The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.

Polypharmacology

Here we use polypharmacology to mean the binding of a drug to multiple target proteins, with clinical effects being mediated through the modulation of the set of protein targets.

Privileged druggable domains

A functional domain of a protein for which a significant fraction of family members have been successfully targeted by drugs. Rhodopsin-like GPCRs, certain ion-channel domains and nuclear receptor ligand-binding domains are clear historical examples of druggable domains.

Prodrug

A drug that requires conversion to a more active pharma-cological form following dosing. This conversion is often performed by endogenous enzymes. Prodrugs are generally used to overcome problems with stability, toxicity or often limited oral bioavailability of the pharmacologically active form.

Rule-of-five

Poor absorption or permeation of a compound is more likely when there are >5 hydrogen bond donors, the molecular mass is >500, cLogP is >5, and the sum of nitrogen and oxygen atoms in a molecule is greater than 10. Many drugs, however, are exceptions to the rule-of-five, and often these are substrates for biological transporters.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Overington, J., Al-Lazikani, B. & Hopkins, A. How many drug targets are there?. Nat Rev Drug Discov 5, 993–996 (2006). https://doi.org/10.1038/nrd2199

Download citation

Further reading

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