Kinetics for Drug Discovery: an industry-driven effort to target drug residence time

Schuetz, Doris A.; Witte, Wilhelmus E. A. de; Wong, Yin Cheong; Knasmueller, Bernhard; Richter, Lars; Kokh, Daria B.; Sadiq, S. Kashif; Bosma, Reggie; Nederpelt, Indira; Heitman, Laura H.; Segala, Elena; Amaral, Marta; Guo, Dong; Andres, Dorothee; Georgi, Victoria; Stoddart, Leigh A.; Hill, Steve J.; Cooke, Robert M.; Graaf, Chris de; Leurs, Rob; Frech, Matthias; Wade, Rebecca C.; Lange, Elizabeth C. M. de; IJzerman, Adriaan P.; Müller‐Fahrnow, Anke; Ecker, Gerhard

doi:10.1016/j.drudis.2017.02.002

Cited by 188 publications

(190 citation statements)

References 112 publications

(135 reference statements)

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“…18−26 In addition, the role of binding kinetics has been explored in forward-thinking programs, such as the K4DD Innovative Medicines Initiative. 27 The present Review reiterates some of the basic concepts that govern drug–target interactions and shows that access to the on and off rates for formation and breakdown of the drug–target complex provides an additional dimension of information that can be used to prioritize drug leads based on kinetic selectivity. Subsequently it is shown that the translation of kinetic effects to time-dependent changes in drug activity depends on target vulnerability which directly impacts kinetic selectivity.…”

Section: Introductionmentioning

confidence: 94%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

222

235

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The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

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Section: Introductionmentioning

confidence: 94%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

222

235

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“…Therefore, the thermodynamic and kinetic measures of binding are linked as K d = k off / k on . However, in most cases, high‐affinity ligands can sometimes exhibit unexpectedly poor pharmacological efficacy in vivo, and a considerable number of approved drugs have manifested nonequilibrium binding characteristics, thereby highlighting why the potential role of drug‐binding kinetics in in vivo efficacy has attracted extensive attention . Here, it should be noted that binding kinetics is only one of many parameters that affect in vivo efficacy of drugs.…”

Section: Computational Methods For Cbddmentioning

confidence: 99%

Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

Zheng

Zhao

Chen

et al. 2018

Medicinal Research Reviews

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Over the past quarter of a century, there has been rapid development in structural biology, which now can provide solid evidence for understanding the functions of proteins. Concurrently, computational approaches with particular relevance to the chemical biology and drug design (CBDD) field have also incrementally and steadily improved. Today, these methods help elucidate detailed working mechanisms and accelerate the discovery of new chemical modulators of proteins. In recent years, integrating computational simulations and predictions with experimental validation has allowed for more effective explorations of the structure, function and modulation of important therapeutic targets. In this review, we summarize the main advancements in computational methodology development, which are then illustrated by several successful applications in CBDD. Finally, we conclude with a discussion of the current major challenges and future directions in the field.

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“…There is a growing understanding that measuring the affinity at equilibrium may not be the best predictor of the in vivo efficacy of a compound, as a number of clinically approved drugs show non‐equilibrium modes of binding (Hothersall, Brown, Dale, & Rawlins, ; Kola & Landis, ; Schuetz et al, ; Waring et al, ). Equilibrium affinity is a function of the association and dissociation rate constants ( K D = k off / k on ) of a molecule binding to a receptor, and compounds with the same affinity can have different association and dissociation rates.…”

Section: Ligand‐binding Kineticsmentioning

confidence: 99%

“…There is a growing understanding that measuring the affinity at equilibrium may not be the best predictor of the in vivo efficacy of a compound, as a number of clinically approved drugs show non-equilibrium modes of binding (Hothersall, Brown, Dale, & Rawlins, 2016;Kola & Landis, 2004;Schuetz et al, 2017;Waring et al, 2015). Equilibrium F I G U R E 2 Measuring ligand binding using fluorescence-or radioactive-based approaches.…”

Section: Ligand-binding Kineticsmentioning

confidence: 99%

Fluorescent ligands: Bringing light to emerging GPCR paradigms

Soave

Briddon

Hill

et al. 2020

British J Pharmacology

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In recent years, several novel aspects of GPCR pharmacology have been described, which are thought to play a role in determining the in vivo efficacy of a compound. Fluorescent ligands have been used to study many of these, which have also required the development of new experimental approaches. Fluorescent ligands offer the potential to use the same fluorescent probe to perform a broad range of experiments, from single‐molecule microscopy to in vivo BRET. This review provides an overview of the in vitro use of fluorescent ligands in further understanding emerging pharmacological paradigms within the GPCR field, including ligand‐binding kinetics, allosterism and intracellular signalling, along with the use of fluorescent ligands to study physiologically relevant therapeutic agents.

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Kinetics for Drug Discovery: an industry-driven effort to target drug residence time

Cited by 188 publications

References 112 publications

Drug–Target Kinetics in Drug Discovery

Drug–Target Kinetics in Drug Discovery

Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

Fluorescent ligands: Bringing light to emerging GPCR paradigms

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