Off-Rate Screening (ORS) By Surface Plasmon Resonance. An Efficient Method to Kinetically Sample Hit to Lead Chemical Space from Unpurified Reaction Products

The dissociation rate constant k d (off-rate) is the component of ligand–protein binding with the most significant potential to enhance compound potency. Here we provide theoretical and empirical data to show that this parameter can be determined accurately from unpurified reaction products containi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-04, Vol.57 (7), p.2845-2850
Main Authors: Murray, James B, Roughley, Stephen D, Matassova, Natalia, Brough, Paul A
Format: Article
Language:English
Subjects:
Biosensing Techniques
Drug Discovery
Drug Evaluation, Preclinical
Humans
Kinetics
Pharmaceutical Preparations - chemistry
Pharmaceutical Preparations - isolation & purification
Small Molecule Libraries - chemistry
Surface Plasmon Resonance - methods
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Summary:The dissociation rate constant k d (off-rate) is the component of ligand–protein binding with the most significant potential to enhance compound potency. Here we provide theoretical and empirical data to show that this parameter can be determined accurately from unpurified reaction products containing designed test compounds. This screening protocol is amenable to parallel chemistry, provides efficiencies of time and materials, and complements existing methodologies for the hit-to-lead phase in fragment-based drug discovery.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401848a