Drug-target Residence Time Research Articles

The dynamics of drug-target interactions: drug-target residence time and its impact on efficacy and safety

The extent and duration of pharmacological action is determined by the lifetime of drug occupancy on a molecular target. This lifetime is defined by dynamic processes that control the rates of drug association and dissociation from the target. Recently, the term residence time has been coined to describe experimental measurements that can be related to the lifetime of the binary drug-target complex, and this in turn to durable, pharmacodynamic activity. The residence time concept and its impact on drug optimization are reviewed here. Examples are provided that demonstrate how a long residence time can improve drug efficacy in vivo. Additionally, optimization of drug-target residence time can help to mitigate off-target mediated toxicity, hence, improving drug safety and tolerability. Recent applications of the residence time concept to both drug discovery and development are also presented.

Erratum: Drug–target residence time and its implications for lead optimization

Nature Reviews Drug Discovery 5, 730–739 (2006); doi:10.1038/nrd2082 The authors wish to correct values in Table 1 and the footnote (page 733). A number of the values in the Table and in the footnote are incompatible with the corresponding data in Figure 2 (page 734). Although these errors affect the quantitative values reported in Table 1, they do not impact on the overarching perspective nor the conclusions drawn in this article.

Drug–target residence time and its implications for lead optimization

Much of drug discovery today is predicated on the concept of selective targeting of particular bioactive macromolecules by low-molecular-mass drugs. The binding of drugs to their macromolecular targets is therefore seen as paramount for pharmacological activity. In vitro assessment of drug-target interactions is classically quantified in terms of binding parameters such as IC(50) or K(d). This article presents an alternative perspective on drug optimization in terms of drug-target binary complex residence time, as quantified by the dissociative half-life of the drug-target binary complex. We describe the potential advantages of long residence time in terms of duration of pharmacological effect and target selectivity.