Measuring drug concentrations where it matters: Developing new models for assessing the true affinity at G protein protein-coupled receptors

When the pharmacology of new drugs is assessed it is assumed that the concentration of drug that the receptor is exposed to is the same as that in bulk aqueous phase. Lipophilic and/or basic drugs can, however, interact directly with the membrane, potentially concentrating drug close to the receptor.

The aim of this project is to directly measure the concentration of drug in and around the membrane and compare this to observed pharmacology, establishing the novel concept of “micro PK/PD relationships” for drugs. This project will utilise a wide variety of techniques, ranging from biophysical confocal imaging and FRET-based kinetic binding through to visualising single cell signalling pathways using state-of-the-art imaging biosensors. The physicochemical properties of compounds will also be assessed, particularly their ability to interact with the phospholipid constituents of membranes. Finally, the parameters obtained from these studies will be used to develop a novel MatLab-based systems model that incorporates local drug concentrations into the pharmacological assessment of binding and signaling kinetics. This will allow us to understand how the non-specific physicochemical properties of ligands can have a profound influence on observed receptor pharmacology and reinforce the need to consider “mico-PK/PD” when developing novel drugs for membrane-bound proteins.