Novel avenues of drug discovery targeting neuropsychiatric, cardiovascular and metabolic disease
G protein-coupled receptors (GPCRs) represent the largest class of medicinal targets. We have developed new approaches for targeting GPCRs using small molecule “allosteric” drugs that bind at spatially distinct sites from those used by the receptor’s natural neurotransmitters and hormones. We apply molecular pharmacology, structural & computational biology, medicinal chemistry and in vivo animal models to understand how allosteric drugs can be translated into medicines for multiple disease states.
Our projects cross academic and industry boundaries:
A) STRUCTURAL BASIS OF ALLOSTERIC DRUG ACTION - We are internationally recognized for applying structural biology to understand the molecular basis of allosteric modulation, and are solving high-resolution GPCR structures to facilitate design of new drugs. We also apply mutagenesis and biophysical methods to yield unprecedented insights into GPCR targets of high therapeutic value in schizophrenia, dementia, reward & addiction, pain, cardiovascular dysfunction and metabolic disease.
B) CHEMICAL BIOLOGY APPROACHES FOR TARGETING GPCRs - These projects involve innovative applications of small molecules, cellular bioassays and imaging to yield new insights into biological processes. Applications include the use of fluorescent, irreversible-binding, allosteric and/or hybrid (multi-pharmacophore) molecules to interrogate or promote new cellular processes that can prove therapeutically useful while minimizing side effects.
C) MODELS OF NEUROPSYCHIATRIC DISEASE - Mental illness remains a leading cause of disability burden in Australia and worldwide. We have established a range of animal models of behavior that are being used to validate the potential for allosteric GPCR drugs to impact positively on a range of neuropsychiatric disorders, in particular schizophrenia and Alzheimer's disease.