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Drug–target residence time and its implications for lead optimization

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  • A Corrigendum to this article was published on 01 March 2007

Abstract

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 IC50 or Kd. 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.

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Acknowledgements

The authors are grateful to D. Yamashita, E. Wood, P. Tummino, Z. Lai, J. Yang, D. Seiffert, R. Gontarek, M. Harpel, B. Brown and V. Schramm for helpful discussions and suggestions.

Author information

Competing interests

The authors are employees of and own stocks in GlaxoSmithKline.

Correspondence to Robert A. Copeland.

Glossary

Association rate constant/on-rate/kon

A second-order rate constant that quantifies the rate at which a free ligand and free receptor combine (through collisional encounters) to form a binary receptor–ligand complex.

Closed system

A system in which the binding partners (ligand and receptor) are present at temporally invariant concentrations throughout the course of an experimental measure.

Cmax

The maximum concentration of drug in systemic circulation that is attained after dosing. The Cmax is typically attained at a specific time point after dosing and this time point is commonly referred to as the tmax.

Dissociation rate constant/off-rate/koff

A first-order rate constant that quantifies the rate at which a binary receptor–ligand complex dissociates to the free ligand and free receptor.

Equilibrium model (of drug action)

A model in which the pharmacological activity of a drug is dependent on the establishment of an equilibrium between the free concentration of drug and the concentration of drug bound to its pharmacological target receptor.

Equilibrium dissociation constant (Kd)

An inverse measure of the affinity of a receptor–ligand pair under equilibrium conditions. The value of Kd is mathematically equivalent to the ratio koff/kon.

Inhibition constant (Ki)

The Ki is the equilibrium dissociation constant for an inhibitor and a specific form of the enzyme target. See Ref. 5 for further information.

Ligand

For the purposes of this review, the term ligand refers to a small molecule, such as a drug, that binds to, and thereby affects the activity of, a specific macromolecular target (receptor).

Non-equilibrium model (of drug action)

Any model in which the pharmacological activity of a drug is most dependent on a departure from equilibrium conditions with respect to the drug and its pharmacological target receptor. See Refs 4,5 for additional information.

Open system

A system in which the concentration(s) of one or more of the binding partners (ligand and receptor) can change over time as molecules of these species enter the system (for example, by distribution to the tissue) and leave the system (for example, by metabolism and other elimination mechanisms).

Receptor

A biological macromolecule responsible for a specific physiological activity that is the target of binding for a particular drug or other ligand.

Binary complex residence time

The amount of time that a ligand resides on a given receptor after binding. Note that this is the definition of residence time used in this article; the term residence time has additional, unrelated meanings (for example, tissue residence time and so on) in other aspects of pharmacology.

IC50

The concentration of a substance that results in a 50% effect on some measure of biochemical function or substance–target binding interaction.

Receptor–ligand complex

(RL). The binary complex between a given receptor and a given ligand. Drug–target complexes are referred to throughout this review as receptor–ligand complexes, regardless of the specific chemical and biochemical nature of the binding partners (for example, enzyme–inhibitor complexes, G-protein coupled-receptor– antagonist complexes, ribosome–antibiotic complexes and so on). In cases of two-step binding mechanisms, RL refers to the initial encounter complex between the receptor and the ligand. In the review an example of a two-step binding mechanism is presented in which the receptor is an enzyme and the ligand is an inhibitor. In such a case the RL complex is more specifically referred to as EI.

RL*

A very high-affinity binary complex between a receptor (for example, an enzyme) and ligand (for example, an enzyme inhibitor) that usually results from isomerization of the receptor (that is, a conformational change) subsequent to initial binding of the ligand to the receptor. In the case of enzyme inhibitors, the initial encounter complex between the enzyme and inhibitor is referred to as EI and the subsequent high-affinity complex is referred to as EI*. See Refs 5,36 for further information.

Structure–activity relationship

(SAR). This term refers to the relationship between the molecular structure of a ligand and its affinity and/or effect on a specific receptor.

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Further reading

Figure 1: Dissociative half-life affects cellular efficacy.
Figure 2: Residence time determines target selectivity.
Figure 3: Relating cell growth inhibition to receptor–ligand interactions.
Figure 4: Extended action of finesteride.