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


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.

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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.


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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.

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Correspondence to Robert A. Copeland.

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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).

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Copeland, R. The drug–target residence time model: a 10-year retrospective. Nat Rev Drug Discov 15, 87–95 (2016).

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