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Drug Discov Today. 2020 Jan;25(1):7-14. doi: 10.1016/j.drudis.2019.09.011. Epub 2019 Sep 23.

The importance of target binding kinetics for measuring target binding affinity in drug discovery: a case study from a CRF1 receptor antagonist program.

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Pharmechanics LLC, 14 Sunnyside Drive South, Owego NY 13827, USA. Electronic address:
Neurocrine Biosciences Inc., 12780 El Camino Real, San Diego, CA 92130, USA.


In drug discovery, it is essential to accurately measure drug-target binding affinity. Here, we revisit the fact that target binding kinetics impact the measurement of affinity, using a case study: development of corticotropin-releasing factor antagonists. Slow dissociation of the drug-target complex results in affinity assays being far from equilibrium, which results in erroneous estimates of affinity. This scenario can impair prediction of human dosing, assessment of target selectivity, identification of high-affinity ligands and determination of SAR. We describe strategies to detect lack of equilibration in affinity assays and methods to correctly measure affinity of slowly dissociating compounds. These considerations will facilitate drug discovery by ensuring reliable measurement of drug-target binding affinity.

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