Discussion

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 review the current methods for measuring receptor kinetics and 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 offers the potential for placing a kinetics assay at the top of a screening cascade, negating the need to first run “IC50 curves” to assess affinity at the receptor. It also presents the opportunity to screen fragment libraries at receptors in a kinetic mode. Finally, the talk will end with a discussion on the concept of “micro pharmacokinetics” and how the local drug concentrations around the receptor must be taken into consideration when interpreting the kinetics of new receptor ligands.