The Role of Binding Kinetics in GPCR Drug Discovery

Swinney, David C.; Haubrich, Brad A.; Liefde, Isabelle Van; Vauquelin, Georges

doi:10.2174/1568026615666150701113054

Cited by 58 publications

(67 citation statements)

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“…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). Such experiments revealed that [ 3 H]-candesartan is also subject to rebinding, and recent simulations suggest that this phenomenon may act as a 'missing link' that allows the overall residence time of this drug to outlast its elimination from the effect compartment [15,16] (Figure 4C and D) [26,34,88]. The reason for this difference is presently unknown and merits further scrutiny.…”

Section: Drug Rebindingmentioning

confidence: 99%

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: Drug Rebindingmentioning

confidence: 99%

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

Vauquelin

2016

Brit J Clinical Pharma

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“…Drug-receptor interactions are traditionally characterized in terms of potency and efficacy in preclinical screening programs; however, increasing evidence suggests that the time molecules reside at their cellular target can provide an important indicator of their clinical performance (Swinney, 2009). In functional assays, these slowly dissociating compounds exhibit the well documented phenomenon of "hemiequilibrium" (Charlton and Vauquelin, 2010), characterized functionally as a depressed agonist response and one that potentially can aid the selection of molecules for further preclinical development.…”

Section: Introductionmentioning

confidence: 99%

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

et al. 2016

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Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. min 21 and 0.048 minute 21 , respectively. Importantly, the k off of QAW039 (half-life 5 14.4 minutes) was .7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD 2 -stimulated [35 S]-GTPgS activation, and its effects were not fully reversed by increasing concentrations of PGD 2 after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor.In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for .180 minutes. All CRTh2 antagonists tested inhibited PGD 2 -stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD 2 -induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD 2 concentrations, which may be clinically relevant.

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“…In particular, ligand-receptor binding kinetics (BK), which have been overlooked in traditional drug discovery approaches, are unprecedentedly emphasized in almost all steps along the drug discovery and development pipeline (1,4,5). Indeed, a statistical analysis on existing drugs demonstrated that the BK profile can be a key differentiator between different drugs (6). Drug-target residence time or dissociative half-life (t 1/2 = 0.693/k off ) has become an important index in lead optimization (4).…”

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confidence: 99%

Free energy landscape for the binding process of Huperzine A to acetylcholinesterase

Bai

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Drug-target residence time (t = 1/k off , where k off is the dissociation rate constant) has become an important index in discovering betteror best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, k off and activation free energy of dissociation (ΔG ≠ off ). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti-Alzheimer's disease drug (−)−Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/ mol. The method also provides atomic resolution information for the (−)−Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery and development.thermodynamics | flexible docking | metastable states | transition states T raditionally, drug discovery is driven by the idea that binders with higher binding affinity to a target should be more efficacious than those with lower binding affinity to the same target (1). It is obvious that the efficacy of a drug is not only associated with thermodynamics but also related to the binding kinetics between the drug and a defined target (2). Numerous examples demonstrated that drug efficacy does not always linearly correlate with binding affinity (3). Therefore, an affinity-based drug discovery approach is less than complete, and an emerging paradigm emphasizing both thermodynamics and kinetics of drug action has been widely recognized and appreciated in drug discovery (1). In particular, ligand-receptor binding kinetics (BK), which have been overlooked in traditional drug discovery approaches, are unprecedentedly emphasized in almost all steps along the drug discovery and development pipeline (1, 4, 5). Indeed, a statistical analysis on existing drugs demonstrated that the BK profile can be a key differentiator between different drugs (6). Drug-target residence time or dissociative half-life (t 1/2 = 0.693/k off ) has become an important index in lead optimization (4). Thus, the BK-based paradigm will be promising in discovering better-or best-in-class drugs (1).Like the experimental approaches for drug discovery, the current computational drug design methods mainly emphasize binding affinity (7-11). Nevertheless, despite more than 30 y of effort, predicting binding free energies for ligands interacting to targets with sufficient accuracy is stil...

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The Role of Binding Kinetics in GPCR Drug Discovery

Cited by 58 publications

References 0 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

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

Free energy landscape for the binding process of Huperzine A to acetylcholinesterase

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