Drug–target residence time and its implications for lead optimization

Copeland, Robert A.; Pompliano, David L.; Meek, Thomas D.

doi:10.1038/nrd2082

Cited by 1,304 publications

(1,456 citation statements)

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“…In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times.…”

Section: Introductionmentioning

confidence: 99%

Section: Drug Rebindingmentioning

confidence: 99%

“…Moreover, the extracellular matrix as well as an unstirred layer of water molecules very close to the membrane constitute further obstacles that may hinder the approach and escape of drugs [83]. A comparable situation also occurs within the cell for drugs that cross the surrounding plasma membrane with some difficulty [7,74,84].As they mimic the complexity of intact tissues, confluent cell monolayers represent convenient surrogate systems for the study of drug rebinding [85][86][87]. Using recombinant Chinese hamster ovary (CHO) cells, we compared the dissociation profiles of different radioligand/receptor combinations in washout experiments in the presence and absence of an excess of unlabelled competitor to estimate the prominence of rebinding [74] (simulated examples are shown in Figure 4A and B).…”

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confidence: 99%

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Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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Section: Introductionmentioning

confidence: 99%

Section: Drug Rebindingmentioning

confidence: 99%

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Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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“…From thermodynamics point of view drugs are acting in an open-system, therefore emphasizing that the recent observations were made under equilibrium conditions is crucial. Under physiological conditions the binding kinetics might also influence the selectivity profile realized in vivo [45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Is there a link between selectivity and binding thermodynamics profiles?

Tarcsay

Keserü

2015

Drug Discovery Today

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“…The relatively high affinity of these inhibitors is due to slow dissociation rates which result in increased drug-target residence times [98] and raise the probability of inhibition of the target under physiological conditions [99]. Furthermore, Type II inhibitors which can bind around the mutation-prone gatekeeper residue receive affinity through additional interactions within the allosteric pocket which is only accessible in the DFG-out state of the kinase [100].…”

Section: Kinase Inhibitors and Conformational Changesmentioning

confidence: 99%

Proteus in the World of Proteins: Conformational Changes in Protein Kinases

Rabiller

Getlik

Klüter

et al. 2010

Archiv der Pharmazie

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The 512 protein kinases encoded by the human genome are a prime example of nature's ability to create diversity by introducing variations to a highly conserved theme. The activity of each kinase domain is controlled by layers of regulatory mechanisms involving different combinations of post-translational modifications, intramolecular contacts, and intermolecular interactions. Ultimately, they all achieve their effect by favoring particular conformations that promote or prevent the kinase domain from catalyzing protein phosphorylation. The central role of kinases in various diseases has encouraged extensive investigations of their biological function and three-dimensional structures, yielding a more detailed understanding of the mechanisms that regulate protein kinase activity by conformational changes. In the present review, we discuss these regulatory mechanisms and show how conformational changes can be exploited for the design of specific inhibitors that lock protein kinases in inactive conformations. In addition, we highlight recent developments to monitor ligand-induced structural changes in protein kinases and for screening and identifying inhibitors that stabilize enzymatically incompetent kinase conformations.

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Drug–target residence time and its implications for lead optimization

Cited by 1,304 publications

References 34 publications

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Is there a link between selectivity and binding thermodynamics profiles?

Proteus in the World of Proteins: Conformational Changes in Protein Kinases

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