2015
DOI: 10.1016/j.bmcl.2015.02.027
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Design strategies to address kinetics of drug binding and residence time

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Cited by 71 publications
(69 citation statements)
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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%
“…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%
“…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%
“…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%