In general, once a receptor drug target has been validated for the treatment of a particular condition, either a high throughput screen is carried out to identify potential hits, or existing drugs or drug candidates are investigated for potential repurposing. Either way, it is beneficial to thoroughly profile the molecular pharmacology of potential drug candidates prior to proceeding towards preclinical development. Do all the candidates have similar affinities/potencies across different binding/signalling assays or is there evidence of bias? Do some candidates result in distinct internalization/trafficking profiling? What does this mean, and do certain profiles correlate with distinct phenotypes observed later in pre-clinical testing? Using such technologies as bioluminescence resonance energy transfer (BRET), it is now possible to carry out profiling in real time and in live cells at a range of ligand concentrations to characterise the ligand binding properties of selected candidates, as well as assessing G protein coupling, arrestin recruitment and the nuances of receptor internalization/trafficking, all particularly relevant for studying the effects on G protein-coupled receptor pharmacology. Receptor tyrosine kinase receptors can also be investigated, utilising proximity to molecules such as Grb2. Heteromerization has considerable potential for modifying receptor pharmacology and so understanding how drug candidates are influenced by heteromerization of the receptor target with other receptors may well also be important.

Learning Objectives:

1. Explain how molecular pharmacology approaches can be used to profile potential drug candidates prior to preclinical development.

2. Explain how receptor internalization/trafficking can be investigated using bioluminescence resonance energy transfer.

3. Explain how heteromerization can influence receptor pharmacology.