The importance of target binding kinetics for measuring target binding affinity in drug discovery: a case study from a CRF 1 receptor antagonist program

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

Abstract

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.

MeSH terms

  • Animals
  • Drug Discovery*
  • Humans
  • Kinetics
  • Protein Binding
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Receptors, Corticotropin-Releasing Hormone / metabolism

Substances

  • Receptors, Corticotropin-Releasing Hormone