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.

The rise of fragment-based drug discovery

Abstract

The search for new drugs is plagued by high attrition rates at all stages in research and development. Chemists have an opportunity to tackle this problem because attrition can be traced back, in part, to the quality of the chemical leads. Fragment-based drug discovery (FBDD) is a new approach, increasingly used in the pharmaceutical industry, for reducing attrition and providing leads for previously intractable biological targets. FBDD identifies low-molecular-weight ligands (150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined using X-ray crystallography or NMR spectroscopy, and is used to facilitate their optimization into potent molecules with drug-like properties. Compared with high-throughput-screening, the fragment approach requires fewer compounds to be screened, and, despite the lower initial potency of the screening hits, offers more efficient and fruitful optimization campaigns. Here, we review the rise of FBDD, including its application to discovering clinical candidates against targets for which other chemistry approaches have struggled.

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: The discovery of AT7519, an inhibitor of cyclin dependent kinases (CDK) 1 and 2.
Figure 2: The discovery of ABT-263, an inhibitor of protein-protein interactions involving Bcl-2 family proteins.

References

  1. 1

    Fattori, D. Molecular recognition: the fragment approach in lead generation. Drug Discov. Today 9, 229–238 (2004).

    CAS  Article  Google Scholar 

  2. 2

    Congreve, M., Chessari, G., Tisi, D. & Woodhead, A. J. Recent developments in fragment-based drug discovery. J. Med. Chem 51, 3661–3680 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Congreve, M., Murray, C. W. & Blundell, T. L. Structural biology and drug discovery. Drug Discov. Today 10, 895–907 (2005).

    CAS  Article  Google Scholar 

  4. 4

    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 Deliv. Rev. 46, 3–26 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb. J. Med. Chem. 51, 817–834 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Leeson, P. D. & Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discov. 6, 881–890 (2007).

    CAS  Article  Google Scholar 

  7. 7

    Teague, S. J., Davis, A. M., Leeson, P. D. & Oprea, T. The design of leadlike combinatorial libraries. Angew. Chem. Int. Ed. 38, 3743–3748 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Vieth, M. et al. Characteristic physical properties and structural fragments of marketed oral drugs. J. Med. Chem. 47, 224–232 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Wenlock, M. C., Austin, R. P., Barton, P., Davis, A. M. & Leeson, P. D. A comparison of physiochemical property profiles of development and marketed oral drugs. J. Med. Chem. 46, 1250–1256 (2003).

    CAS  Article  Google Scholar 

  10. 10

    Hughes, J. D. et al. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg. Med. Chem. Lett. 18, 4872–4875 (2008).

    CAS  Article  Google Scholar 

  11. 11

    Jencks, W. P. On the attribution and additivity of binding energies. Proc. Natl Acad. Sci. USA 78, 4046–4050 (1981).

    CAS  Article  Google Scholar 

  12. 12

    Page, M. I. & Jencks, W. P. Entropic contributions to rate accelerations in enzymic and intramolecular reactions and the chelate effect. Proc. Natl Acad. Sci. USA 68, 1678–1683 (1971).

    CAS  Article  Google Scholar 

  13. 13

    Murray, C. W. & Verdonk, M. L. The consequences of translational and rotational entropy lost by small molecules on binding to proteins. J. Comput. Aided Mol. Des. 16, 741–753 (2002).

    CAS  Article  Google Scholar 

  14. 14

    Finkelstein, A. V. & Janin, J. The price of lost freedom: entropy of bimolecular complex formation. Protein Eng. 3, 1–3 (1989).

    CAS  Article  Google Scholar 

  15. 15

    Carr, R. A., Congreve, M., Murray, C. W. & Rees, D. C. Fragment-based lead discovery: leads by design. Drug Discov. Today 10, 987–992 (2005).

    CAS  Article  Google Scholar 

  16. 16

    Hopkins, A. L., Groom, C. R. & Alex, A. Ligand efficiency: a useful metric for lead selection. Drug Discov. Today 9, 430–431 (2004).

    Article  Google Scholar 

  17. 17

    Kuntz, I. D., Chen, K., Sharp, K. A. & Kollman, P. A. The maximal affinity of ligands. Proc. Natl Acad. Sci. USA 96, 9997–10002 (1999).

    CAS  Article  Google Scholar 

  18. 18

    Congreve, M., Carr, R., Murray, C. & Jhoti, H. A 'rule of three' for fragment-based lead discovery? Drug Discov. Today 8, 876–877 (2003).

    Article  Google Scholar 

  19. 19

    Abad-Zapatero, C. & Metz, J. T. Ligand efficiency indices as guideposts for drug discovery. Drug Discov. Today 10, 464–469 (2005).

    Article  Google Scholar 

  20. 20

    Hajduk, P. J. Fragment-based drug design: how big is too big? J. Med. Chem. 49, 6972–6976 (2006).

    CAS  Article  Google Scholar 

  21. 21

    Hann, M. M., Leach, A. R. & Harper, G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci. 41, 856–864 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Leach, A. R., Hann, M. M., Burrows, J. N. & Griffen, E. J. Fragment screening: an introduction. Mol. Biosyst. 2, 430–446 (2006).

    Article  Google Scholar 

  23. 23

    Fink, T., Bruggesser, H. & Reymond, J. L. Virtual exploration of the small-molecule chemical universe below 160 Daltons. Angew. Chem. Int. Ed. 44, 1504–1508 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Fink, T. & Reymond, J. L. Virtual exploration of the chemical universe up to 11 atoms of C, N, O, F: Assembly of 26.4 million structures (110.9 million stereoisomers) and analysis for new ring systems, stereochemistry, physicochemical properties, compound classes, and drug discovery. J. Chem. Inf. Model. 47, 342–353 (2007).

    CAS  Article  Google Scholar 

  25. 25

    Bohacek, R. S., Mcmartin, C. & Guida, W. C. The art and practice of structure-based drug design: a molecular modeling perspective. Med. Res. Rev. 16, 3–50 (1996).

    CAS  Article  Google Scholar 

  26. 26

    Ertl, P. Cheminformatics analysis of organic substituents: identification of the most common substituents, calculation of substituent properties, and automatic identification of drug-like bioisosteric groups. J. Chem. Inf. Comput. Sci. 43, 374–380 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Schuffenhauer, A. et al. Library design for fragment based screening. Curr. Top. Med. Chem. 5, 751–762 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Erlanson, D. A., McDowell, R. S. & O'Brien, T. Fragment-based drug discovery. J. Med. Chem. 47, 3463–3482 (2004).

    CAS  Article  Google Scholar 

  29. 29

    Rees, D. C., Congreve, M., Murray, C. W. & Carr, R. Fragment-based lead discovery. Nat. Rev. Drug Discov. 3, 660–672 (2004).

    CAS  Article  Google Scholar 

  30. 30

    Hesterkamp, T. & Whittaker, M. Fragment-based activity space: smaller is better. Curr. Opin. Chem. Biol. 12, 260–268 (2008).

    CAS  Article  Google Scholar 

  31. 31

    Saxty, G. et al. Identification of inhibitors of protein kinase B using fragment-based lead discovery. J. Med. Chem. 50, 2293–2296 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Wyatt, P. G. et al. Identification of N-(4-piperidinyl)-4-(2, 6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design. J. Med. Chem. 51, 4986–4999 (2008).

    CAS  Article  Google Scholar 

  33. 33

    Gill, A. L., Verdonk, M., Boyle, R. G. & Taylor, R. A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr. Top. Med. Chem. 7, 1408–1422 (2007).

    CAS  Article  Google Scholar 

  34. 34

    Shuker, S. B., Hajduk, P. J., Meadows, R. P. & Fesik, S. W. Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 1531–1534 (1996).

    CAS  Article  Google Scholar 

  35. 35

    Wells, J. A. & McClendon, C. L. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450, 1001–1009 (2007).

    CAS  Article  Google Scholar 

  36. 36

    Congreve, M., Chessari, G., Tisi, D. & Woodhead, A. J. Recent developments in fragment-based drug discovery. J. Med. Chem. 51, 3661–3680 (2008).

    CAS  Article  Google Scholar 

  37. 37

    Hajduk, P. J. & Greer, J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat. Rev. Drug Discov. 6, 211–219 (2007).

    CAS  Article  Google Scholar 

  38. 38

    Ciulli, A., Williams, G., Smith, A. G., Blundell, T. L. & Abell, C. Probing hot spots at protein-ligand binding sites: a fragment-based approach using biophysical methods. J. Med. Chem. 49, 4992–5000 (2006).

    CAS  Article  Google Scholar 

  39. 39

    Huang, J. W. et al. Fragment-based design of small molecule x-linked inhibitor of apoptosis protein inhibitors. J. Med. Chem. 51, 7111–7118 (2008).

    CAS  Article  Google Scholar 

  40. 40

    Ciulli, A. & Abell, C. Fragment-based approaches to enzyme inhibition. Curr. Opin. Biotechnol. 18, 489–496 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Czaplewski, L. G. et al. Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ. Bioorg. Med. Chem. Lett. 19, 524–527 (2009).

    CAS  Article  Google Scholar 

  42. 42

    Haydon, D. J. et al. An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 321, 1673–1675 (2008).

    CAS  Article  Google Scholar 

  43. 43

    Hartshorn, M. J. et al. Fragment-based lead discovery using X-ray crystallography. J. Med. Chem. 48, 403–413 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Babaoglu, K. & Shoichet, B. K. Deconstructing fragment-based inhibitor discovery. Nat. Chem. Biol. 2, 720–723 (2006).

    CAS  Article  Google Scholar 

  45. 45

    Hajduk, P. J. & Greer, J. A decade of fragment-based drug design: strategic advances and lessons learned. Nat. Rev. Drug Discov. 6, 211–219 (2007).

    CAS  Article  Google Scholar 

  46. 46

    Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005).

    CAS  Article  Google Scholar 

  47. 47

    Petros, A. M. et al. Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J. Med. Chem. 49, 656–663 (2006).

    CAS  Article  Google Scholar 

  48. 48

    Bruncko, M. et al. Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J. Med. Chem. 50, 641–662 (2007).

    CAS  Article  Google Scholar 

  49. 49

    Wendt, M. D. et al. Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo. J. Med. Chem. 49, 1165–1181 (2006).

    CAS  Article  Google Scholar 

  50. 50

    Park, C. M. et al. Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J. Med. Chem. 51, 6902–6915 (2008).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We acknowledge all Astex scientists past and present and Harren Jhoti and Chris Abell for helpful comments on the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to David C. Rees.

Ethics declarations

Competing interests

The authors are employees of Astex Therapeutics, a drug discovery company that uses fragment-based drug discovery.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Murray, C., Rees, D. The rise of fragment-based drug discovery. Nature Chem 1, 187–192 (2009). https://doi.org/10.1038/nchem.217

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