Understanding the molecular basis and physiological consequences of allosteric modulation and biased agonism at G protein-coupled receptors
A key focus of our laboratory is on the interpretation of drug actions in terms of underlying hypothetical mechanisms. This involves the combination of appropriately designed bioassays, either at the cellular or whole tissue level, with mathematical models that can shed light on the molecular properties of drugs in a manner that allows novel predictions to be made about the compounds or target(s) under investigation. An application of quantitative models of drug action is particularly relevant to understanding allosteric modulation and biased agonism at GPCRs, and we are constantly aiming to develop new approaches that can lead to more informative experimental design and therapeutic agents with improved biological properties.
Structural and Computational Biology
We are very interested in understanding the molecular, and even atomistic, basis of how drugs can interact with GPCRs to modulate their biology, and how this information can be exploited to facilitate structure-based drug design. To address this, we utilize mutagenesis, biophysical techniques, x-ray crystallography, cryo-electron microscopy (cryo-EM) and cutting-edge computational modelling and docking methods to understand receptor dynamics and drug-receptor interactions, especially in the context of allosteric modulators and biased agonists.
Chemical and Cellular Biology
We have numerous projects that sit at the interface of chemistry and biology, using small-molecules to interrogate GPCRs and their associated signalling pathways. These studies focus on the generation of novel chemical probes as tools to illuminate biological processes, as well as the discovery of potential therapeutic leads that can progress in drug discovery programs. Our main focus in this regard is in the optimization of structure-activity relationships underlying allosteric modulators and biased agonist activity. To achieve this, we combine analytical pharmacology with medicinal chemistry, resonance energy transfer techniques and multi-tiered signal transduction assays that encompass a broad range of cellular activities, including assays of intracellular second messengers, protein-protein interactions, trafficking, reporter genes, whole cell metabolism and morphological changes. These are performed in both recombinant and native cells, with a view to predicting optimal behaviours for perturbing whole organ systems in a therapeutic setting.
Animal Models of Physiology and Disease
We strive to translate our knowledge of GPCR structure, function and signalling into a deep understanding of the mechanisms of physiological regulation and disease. A main thrust of our laboratory in this regard is to understand how allosteric modulators and biased agonists can be used to treat neurological, metabolic and other diseases. We utilize a suite of animal models of behaviour or metabolic dysfunction, including studies in transgenic mice where key proteins have been removed or modified to understand the physiological and pathophysiological relevance of allosteric modulation and biased agonism. We are particularly interested in the potential for untapped endogenous allosteric and biased ligands in both health and disease.