Exhibitor Tutorial
A TR-FRET approach to measure the kinetics of ligand-receptor binding and its application to kinetic fragment screening
Tuesday, February 6
12:30 PM - 1:15 PM
Location: Room 5A
CW
SC
Steven Charlton
Professor of Molecular Pharmacology and Drug Discovery
School of Life Sciences, Queen's Medical Centre, University of Nottingham
Optimizing the receptor binding kinetics of new drugs can have significant benefits, ranging from improved duration of action to enhanced efficacy through the insurmountable antagonism of dynamic physiological systems. It is also becoming apparent that binding kinetics plays a role in the phenomenon of biased agonism. Despite this, the kinetics of new receptor ligands are rarely measured early in the drug discovery process, largely because current assays are technically difficult and relatively low-throughput.
This talk will introduce the potential clinical benefits of optimising binding kinetics and review the current methods for measuring kinetic parameters. It will then describe the development of a novel approach using time-resolved FRET in continuous read mode that is capable of simultaneously measuring the kinetics of hundreds of compounds. This enables kinetics assays to be placed at the top of a screening cascade, negating the need to first run “IC50 curves” to assess affinity at the receptor. It also offers the opportunity to measure the kinetics of low affinity compounds, making it an ideal platform for fragment screening. This will be exemplified by describing a fragment screening campaign that was recently run in kinetic mode at the dopamine D2 receptor.
