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 drug–target residence time model: a 10-year retrospective

Abstract

The drug–target residence time model was first introduced in 2006 and has been broadly adopted across the chemical biology, biotechnology and pharmaceutical communities. While traditional in vitro methods view drug–target interactions exclusively in terms of equilibrium affinity, the residence time model takes into account the conformational dynamics of target macromolecules that affect drug binding and dissociation. The key tenet of this model is that the lifetime (or residence time) of the binary drug–target complex, and not the binding affinity per se, dictates much of the in vivo pharmacological activity. Here, this model is revisited and key applications of it over the past 10 years are highlighted.

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: Kinetic aspects of drug-target interactions in vitro and in vivo.
Figure 2: Drug affinity (target potency) is often driven by drug–target residence time.
Figure 3: The retrograde induced-fit mechanism of drug-target dissociation.
Figure 4: In vivo efficacy often depends on drug-target residence time.

References

  1. 1

    Copeland, R. A., Pompliano, D. L. & Meek, T. D. Drug–target residence time and its implications for lead optimization. Nat. Rev. Drug Discov. 5, 730–739 (2006).

    CAS  Article  Google Scholar 

  2. 2

    Tummino, P. J. & Copeland, R. A. Residence time of receptor–ligand complexes and its effect on biological function. Biochemistry 47, 5481–5492 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Copeland, R. A. The dynamics of drug–target interactions: drug–target residence time and its impact on efficacy and safety. Expert Opin. Drug Discov. 5, 305–310 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Copeland, R. A. Conformational adaptation in drug–target interactions and residence time. Future Med. Chem. 3, 1491–1501 (2011).

    CAS  Article  Google Scholar 

  5. 5

    Copeland, R. A. Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Wiley, 2013).

    Book  Google Scholar 

  6. 6

    Schiele, F., Ayaz, P. & Fernandez-Montalvan, A. A universal homogeneous assay for high-throughput determination of binding kinetics. Anal. Biochem. 468, 42–49 (2014).

    Article  Google Scholar 

  7. 7

    Zhang, R. & Windsor, W. T. in Antiviral Methods and Protocols, Methods in Molecular Biology (ed. Gong, E. Y.) 59–79 (2013).

    Book  Google Scholar 

  8. 8

    Copeland, R. A. et al. Mechanism of selective inhibition of the inducible isoform of prostaglandin G/H synthase. Proc. Natl Acad. Sci. USA 91, 11202–11206 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Bull, H. G. et al. Mechanism-based inhibition of human steroid 5α-reductase by finasteride: enzyme catalyzed formation of NADP-dihydrofinasteride, a potent bisubstrate analog inhibitor. J. Am. Chem. Soc. USA 118, 2359–2365 (1996).

    CAS  Article  Google Scholar 

  10. 10

    Gooljarsingh, L. T. et al. A biochemical rationale for the anticancer effects of HSP90 inhibitors: slow, tight binding inhibition by geldanamycin and its analogues. Proc. Natl Acad. Sci. USA 103, 7625–7630 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Morrison, J. F. & Walsh, C. T. The behavior and significance of slow-binding enzyme inhibitors. Adv. Enzymol. Relat. Areas Mol. Biol. 61, 201–299 (1988).

    CAS  PubMed  Google Scholar 

  12. 12

    Danielson, U. H. Integrating surface plasmon resonance biosensor-based interaction kinetic analyses into the lead discovery and optimization process. Future Med. Chem. 1, 1399–1414 (2009).

    CAS  Article  Google Scholar 

  13. 13

    Dahl, G. & Akerud, T. Pharmacokinetics and the drug–target residence time concept. Drug Discov. Today 18, 697–707 (2013).

    CAS  Article  Google Scholar 

  14. 14

    Zhang, R. & Monsma, F. The importance of drug–target residence time. Curr. Opin. Drug Discov. 12, 488–496 (2009).

    CAS  Google Scholar 

  15. 15

    Lu, H. & Tonge, P. J. Drug–target residence time: critical information for lead optimization. Curr. Opin. Chem. Biol. 14, 467–474 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Hyre, D. E. et al. Cooperative hydrogen bond interactions in the streptavidin–biotin system. Protein Sci. 15, 459–467 (2006).

    CAS  Article  Google Scholar 

  17. 17

    Maschera, B. et al. Human immunodeficiency virus: mutations in the viral protease that confer resistance to saquinavir increase the dissociation rate constant of the protease–saquinavir complex. J. Biol. Chem. 271, 33231–33235 (1996).

    CAS  Article  Google Scholar 

  18. 18

    Basavapathruni, A. et al. Conformational adaption drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chem. Biol. Drug Des. 80, 971–980 (2012).

    CAS  Article  Google Scholar 

  19. 19

    Schneider, E. V., Bottcher, J., Huber, R., Maskos, K. & Neumann, L. Structure–kinetic relationship study of CDK8/CycC specific compounds. Proc. Natl Acad. Sci. USA 110, 8081–8086 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Zhang, R. Which trails are your drugs taking? Nat. Chem. Biol. 11, 382–383 (2015).

    CAS  Article  Google Scholar 

  21. 21

    Markgren, P.-O. et al. Relationships between structure and interaction kinetics for HIV-protease inhibitors. J. Med. Chem. 45, 5430–5439 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Vauquelin, G. Rebinding: or why drugs may act longer in vivo than expected from their in vitro target residence time. Expert Opin. Drug Discov. 5, 927–941 (2010).

    CAS  Article  Google Scholar 

  23. 23

    Vauquelin, G. & Charlton, S. J. Long-lasting target binding and rebinding as mechanisms to prolong in vivo drug action. Br. J. Pharmacol. 161, 488–508 (2010).

    CAS  Article  Google Scholar 

  24. 24

    Li, H.-J. et al. A structural and energetic model for the slow-onset inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA. ACS Chem. Biol. 9, 986–993 (2014).

    CAS  Article  Google Scholar 

  25. 25

    Lai, C.-T. et al. Rational modulation of the induced-fit conformational change for slow-onset inhibition of Mycobacterium tuberculosis InhA. Biochemistry 54, 4683–4691 (2015).

    CAS  Article  Google Scholar 

  26. 26

    Tiwary, P., Limongelli, V., Salvalaglio, M. & Parrinello, M. Kinetics of protein–ligand unbinding: predicting pathways, rates and rate-limiting steps. Proc. Natl Acad. Sci. USA 112, E386–E391 (2009).

    Article  Google Scholar 

  27. 27

    Cusack, K. P. et al. Design strategies to address kinetics of drug binding and residence time. Bioorg. Med. Chem. Lett. 25, 2019–2027 (2015).

    CAS  Article  Google Scholar 

  28. 28

    Van Aller, G. et al. Long residence time inhibition of EZH2 in activated polycomb repressive complex 2. ACS Chem. Biol. 9, 622–629 (2014).

    CAS  Article  Google Scholar 

  29. 29

    Chan-Penebre, E. et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat. Chem. Biol. 11, 432–437 (2015).

    CAS  Article  Google Scholar 

  30. 30

    Lu, H. et al. Slow-onset inhibition of the FabI enoyl reductase from Francisella tularensis: residence time and in vivo activity. ACS Chem. Biol. 4, 221–231 (2009).

    CAS  Article  Google Scholar 

  31. 31

    Guo, D., Mulder-Krieger, T., Ijzerman, A. P. & Heitman, L. H. Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time. Br. J. Pharmacol. 166, 1846–1859 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Sullivan, S. M. & Holyoak, T. Enzymes with lid-gated active sites must operate by an induced fit mechanism instead of conformational selection. Proc. Natl Acad. Sci. USA 105, 13829–13834 (2008).

    CAS  Article  Google Scholar 

  33. 33

    Garvey, E. P. et al. Potent inhibitors of HIV-1 integrase display a two-step, slow-binding inhibition mechanism which is absent in a drug-resistant T661/M1541 mutant. Biochemistry 48, 1644–1653 (2009).

    CAS  Article  Google Scholar 

  34. 34

    González, B. et al. The crystal structure of tetrameric methionine adenosyltransferase from rat liver reveals the methionine-binding site. J. Mol. Biol. 300, 363–375 (2000).

    Article  Google Scholar 

  35. 35

    Pearce, F. G. & Andrews, T. J. The relationship between side reactions and slow inhibition of ribulose-bisphosphate carboxylase revealed by a loop 6 mutant of the tobacco enzyme. J. Biol. Chem. 278, 32526–32536 (2003).

    CAS  Article  Google Scholar 

  36. 36

    Liu, Y. et al. Hepatitis C NS3 protease inhibition by peptidyl-α-ketoamide inhibitors: kinetic mechanism and structure. Arch. Biochem. Biophys. 421, 207–216 (2004).

    CAS  Article  Google Scholar 

  37. 37

    Kapoor, M. et al. Kinetic and structural analysis of the increased affinity of enoyl-ACP (acyl-carrier protein) reductase for triclosan in the presence of NAD. Biochem. J. 381, 725–733 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Carroll, M. J. et al. Evidence for dynamics in proteins as a mechanism for ligand dissociation. Nat. Chem. Biol. 8, 246–252 (2012).

    CAS  Article  Google Scholar 

  39. 39

    Luckner, S. R. et al. A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis. J. Biol. Chem. 285, 14330–14337 (2010).

    CAS  Article  Google Scholar 

  40. 40

    Cowan-Jacob, S. W., Mobitz, H. & Fabbro, D. Structural biology contributions to tyrosine kinase drug discovery. Curr. Opin. Cell Biol. 21, 280–287 (2009).

    CAS  Article  Google Scholar 

  41. 41

    Luong, C. et al. Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2. Nat. Struct. Biol. 3, 927–933 (1996).

    CAS  Article  Google Scholar 

  42. 42

    Schmidtke, P., Luque, F. J., Murray, J. B. & Barril, X. Shielded hydrogen bonds as structural determinants of binding kinetics: application in drug design. J. Am. Chem. Soc. 133, 18903–18910 (2011).

    CAS  Article  Google Scholar 

  43. 43

    Bradshaw, J. M. et al. Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat. Chem. Biol. 11, 525–531 (2015).

    CAS  Article  Google Scholar 

  44. 44

    Walkup, G. K. et al. Translating slow-binding inhibition kinetics into cellular and in vivo effects. Nat.Chem. Biol. 11, 416–423 (2015).

    CAS  Article  Google Scholar 

  45. 45

    Billheimer, J. T. et al. Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated. Blood 99, 3540–3546 (2002).

    CAS  Article  Google Scholar 

  46. 46

    Seiffert, D. et al. Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia. Blood 101, 58–63 (2003).

    CAS  Article  Google Scholar 

  47. 47

    Norman, A. W., Mizwicki, M. T. & Norman, D. P. Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model. Nat. Rev. Drug Discov. 3, 27–41 (2004).

    CAS  Article  Google Scholar 

  48. 48

    Kapur, S. & Seeman, P. Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. J. Psychiatry Neurosci. 25, 161–166 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Vauquelin, G., Bostoen, S., Vanderheyden, P. & Seeman, P. Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism. Naunyn Schmiedebergs Arch. Pharmacol. 385, 337–372 (2012).

    CAS  Article  Google Scholar 

  50. 50

    Swinney, D. C. Biochemical mechanisms of drug action: what does it take for success? Nat. Rev. Drug Discov. 3, 801–808 (2004).

    CAS  Article  Google Scholar 

  51. 51

    Swinney, D. C. Molecular mechanism of action (MMoA) in drug discovery. Annu. Reports Med. Chem. 46, 301–317 (2011).

    CAS  Article  Google Scholar 

  52. 52

    Keseru, G. M. & Swinney, D. C. Thermodynamics and Kinetics of Drug Binding (Wiley-VCH, 2015).

    Book  Google Scholar 

  53. 53

    Ploeger, B. A., van der Graaf, P. H. & Danhof, M. Incorporating receptor theory in mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling. Drug Metab. Pharmacokinet. 29, 84–93 (2009).

    Google Scholar 

  54. 54

    Tillotson, B. et al. Hsp90 (heat shock protein 90) inhibitor occupancy is a direct determinant of client protein degradation and tumor growth arrest in vivo. J. Biol. Chem. 285, 39835–39843 (2010).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The author thanks the many colleagues who have contributed to the development and application of the drug–target residence time model since its initial inception. In particular the author thanks the following scientists for their significant contributions to the development of the model: C. T. Walsh, D. Swinney, P. Tonge, P. Tummino, S. Fisher, G. Walkup, G. Vauquelin, H. Danielson, D. Pompliano and T. Meek.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Robert A. Copeland.

Ethics declarations

Competing interests

R.A.C. is an employee of and shareholder in Epizyme, Inc. (USA). The author also serves on the scientific advisory boards of Mersana Therapeutics (USA) and Raze Therapeutics (USA).

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Copeland, R. The drug–target residence time model: a 10-year retrospective. Nat Rev Drug Discov 15, 87–95 (2016). https://doi.org/10.1038/nrd.2015.18

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