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Determination of Affinity and Residence Time of Potent Drug-Target Complexes by Label-free Biosensing.

Abstract：

:Prolonged drug-target occupancy has become increasingly important in lead optimization, and biophysical assays that measure residence time are in high demand. Here we report a practical label-free assay methodology that provides kinetic and affinity measurements suitable for most target classes without long preincubations and over comparatively short sample contact times. The method, referred to as a "chaser" assay, has been applied to three sets of unrelated kinase/inhibitor panels in order to measure the residence times, where correlation with observed efficacy was suspected. A lower throughput chaser assay measured a residence time of 3.6 days ±3.4% (95% CI) and provided single digit pM sensitivity. A higher throughput chaser methodology enabled a maximum capacity of 108 compounds in duplicate/day with an upper residence time limit of 9 h given an assay dissociation time of 34 min.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Quinn JG,Pitts KE,Steffek M,Mulvihill MM

doi

10.1021/acs.jmedchem.7b01829

subject

Has Abstract

pub_date

2018-06-28 00:00:00

pages

5154-5161

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

杂志文章

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