Design strategies to address kinetics of drug binding and residence time

Cusack, Kevin P.; Wang, Ying; Hoemann, Michael Z.; Marjanovic, Jasmina; Heym, Roland G.; Vasudevan, Anil

doi:10.1016/j.bmcl.2015.02.027

Cited by 70 publications

(69 citation statements)

References 79 publications

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“…The results of our in vivo study provide direct evidence that high receptor occupancy might be one of the key factors to improve the translation from in vitro findings into in vivo efficacy in inflammatory diseases. In addition, our findings in the in vitro study support the need of characterizing the affinity and kinetic profile of drug candidates in multiple species, as a way to improve preclinical and clinical translation of efficacy and safety findings 12, 41 . To conclude, the CCR2 antagonist 15a emerges as a potential candidate for further drug development to inhibit atherosclerotic lesion development and progression, and may also be of therapeutic value for other diseases involving CCR2.…”

Section: Discussionsupporting

confidence: 60%

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

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Zacarı́as

Witte

et al. 2017

Sci Rep

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CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model. First, radioligand binding assays were performed to determine affinity and binding kinetics of 15a on murine CCR2. To assess the in vivo efficacy, western-type diet fed apoE−/− mice were treated daily with 15a or vehicle as control. Treatment with 15a reduced the amount of circulating CCR2+ monocytes and the size of the atherosclerotic plaques in both the carotid artery and the aortic root. We then showed that the long pharmacokinetic half-life of 15a combined with the high drug concentrations ensured prolonged CCR2 occupancy. These data render 15a a promising compound for drug development and confirms high receptor occupancy as a key parameter when targeting chemokine receptors.

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Section: Discussionsupporting

confidence: 60%

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

Bot

Zacarı́as

Witte

et al. 2017

Sci Rep

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“…In conclusion, drug rebinding may be regarded to be a natural consequence of hindered three‐dimensional diffusion because of the morphological properties of our tissues and cells as well as of local target accumulation within cells or on their membranes. Taking account of this phenomenon could therefore be of help to design in vitro binding kinetic assays that are more relevant and translatable to in vivo settings (Cusack et al ., ; Zhang, ). Although the present simulations should only be regarded to provide a ‘proof of principle’, the results obtained suggest that k on merits more consideration in drug design because of its important contribution to robust rebinding.…”

Section: Discussionmentioning

confidence: 99%

Effects of target binding kinetics on in vivo drug efficacy: k_off, k_on and rebinding

Vauquelin

2016

British J Pharmacology

102

103

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BACKGROUND AND PURPOSEOptimal drug therapy often requires continuing high levels of target occupancy. Besides the traditional pharmacokinetic contribution, target binding kinetics is increasingly considered to play an important role as well. While most attention has been focused on the dissociation rate of the complex, recent reports expressed doubt about the unreserved translatability of this pharmacodynamic property into clinical efficacy. 'Micro'-pharmacokinetic mechanisms like drug rebinding and partitioning into the cell membrane may constitute a potential fix. EXPERIMENTAL APPROACHSimulations were based on solving differential equations. KEY RESULTSBased on a selected range of association and dissociation rate constants, k on and k off , and rebinding potencies of the drugs as variables, their effects on the temporal in vivo occupancy profile of their targets, after one or multiple repetitive dosings, have here been simulated. CONCLUSIONS AND IMPLICATIONSMost strikingly, the simulations show that, when rebinding is also taken into account, increasing k on may produce closely the same outcome as decreasing k off when dosing is performed in accordance with the therapeutically most relevant constant [L max ]/K D ratio paradigm. Also, under certain conditions, rebinding may produce closely the same outcome as invoking slow diffusion of the drug between the plasma compartment and a target-containing 'effect' compartment. Although the present simulations should only be regarded as a 'proof of principle', these findings may help pharmacologists and medicinal chemists to devise ex vivo and in vitro binding kinetic assays that are more relevant and translatable to in vivo settings.Abbreviations k on , k off , second-and first-order rate constants for association and dissociation; k a , k e , first-order rate constants for the inflow and elimination/clearance of the drug; k eo , first-order rate constant for the drug's equilibration between the plasma and effect compartments; [L]

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“…Photobleaching of the acceptor may still be a matter of concern for FRET and BRET, but their replacement by self‐healing fluorophores (Tinnefeld and Cordes, ) could further enhance their performance. Also, it should be checked whether or not the covalent coupling of an acceptor to the ligand affects its pharmacological properties (Cusack et al , ). Label‐free assays: surface plasmon resonance (SPR) measures changes in the refractive index of the medium nearby the sensor's thin metal surface when a ligand or receptor in solution increases the mass at that surface by binding to its immobilized counterpart (Patching, ). SPR has become a leading approach for characterizing the kinetics of molecular interactions, but for membrane‐associated receptors, a major challenge is that they have to be solubilized and purified in order to be being immobilized.…”

Section: Technical Considerationsmentioning

confidence: 99%

On the different experimental manifestations of two‐state ‘induced‐fit’ binding of drugs to their cellular targets

Vauquelin

Liefde

Swinney

2016

British J Pharmacology

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'Induced-fit' binding of drugs to a target may lead to high affinity, selectivity and a long residence time, and this mechanism has been proposed to apply to many drugs with high clinical efficacy. It is a multistep process that initially involves the binding of a drug to its target to form a loose RL complex and a subsequent isomerization/conformational change to yield a tighter binding R'L state. Equations with the same mathematical form may also describe the binding of bivalent antibodies and related synthetic drugs. Based on a selected range of 'microscopic' rate constants and variables such as the ligand concentration and incubation time, we have simulated the experimental manifestations that may go along with induced-fit binding. Overall, they validate different experimental procedures that have been used over the years to identify such binding mechanisms. However, they also reveal that each of these manifestations only becomes perceptible at particular combinations of rate constants. The simulations also show that the durable nature of R'L and the propensity of R'L to be formed repeatedly before the ligand dissociates will increase the residence time. This review may help pharmacologists and medicinal chemists obtain preliminary indications for identifying an induced-fit mechanism. Abbreviations[L], concentration of ligand in bulk of solution; RL and R'L, loose and tight binding ligand-receptor complexes; △G o , difference in Gibbs free energy between R and R'L; k 1 , k 2 … k 1A … k 1M …, microscopic rate constants; k obs , k on , k off , macroscopic rate constants for association and dissociation; K D , 'thermodynamic' equilibrium dissociation constant based on △G o ; K D *, [L] at which this observed binding is half-maximal at equilibrium; app K D *, [L] at which the observed binding is half-maximal under earlier non-equilibrium conditions; p, -LogThese Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology. org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (Alexander et al., 2015.

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Design strategies to address kinetics of drug binding and residence time

Cited by 70 publications

References 79 publications

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

Effects of target binding kinetics on in vivo drug efficacy: k_off, k_on and rebinding

On the different experimental manifestations of two‐state ‘induced‐fit’ binding of drugs to their cellular targets

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Design strategies to address kinetics of drug binding and residence time

Cited by 70 publications

References 79 publications

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

Effects of target binding kinetics on in vivo drug efficacy: koff, kon and rebinding

On the different experimental manifestations of two‐state ‘induced‐fit’ binding of drugs to their cellular targets

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Effects of target binding kinetics on in vivo drug efficacy: k_off, k_on and rebinding