Drug Discovery Biology


Eastern Health Clinical SchoolNursing and MidwiferyPrimary Health CareCommunity Emergency Health and Paramedic PracticeSchool of Psychology and PsychiatryThe optimum functioning of living cells, and consequently the health of the entire organism, depends on how cells respond to the multitude of physical and chemical stimuli that continually bombard them. The majority of all chemical cellular stimuli are comprised of hormones and neurotransmitters that impart their actions by binding to specific cell surface receptor proteins. G protein coupled receptors (GPCRs) represent the largest superfamily of all receptors (approx. 2% of the human genome) and are the targets for nearly 50% of all currently used therapeutic drugs. The principal direction of our laboratory is towards understanding novel modes of regulation of GPCRs in an effort to identify novel targets or approaches for drug http:... discovery. Our work encompasses investigation across virtually all levels of GPCR structure/function, including analysis of the functional significance of single nucleotide polymorphisms, RNA editing and alternate mRNA splicing; signaling via G proteins and downstream messenger [url=http://www.broncosofficialonlinestore.com/Lamin_Barrow_Jersey_Broncos]Authe... Lamin Barrow Jersey systems; interaction of receptors with regulatory accessory proteins; novel allosteric GPCR binding sites, and mathematical and molecular modelling of GPCR Bradl... Roby Authentic Jersey ligand interactions. Approaches that we use include, generation of chimeric receptors, site directed mutagenesis, photoaffinity labelling, resonance energy transfer and three dimensional molecular modelling.


Theme 2. Allosteric modulation of GPCRs


Our laboratory is an international leader in the study of mechanisms of allosteric modulation of GPCRs by small molecules. Allosteric ligands bind to the receptor at a site topographically separate from the orthosteric site used by the endogenous ligand . We have developed methods for assaying, validating and quantifying the properties of such ligands in a manner that can facilitate understanding of structure activity relationships and assay development an [url=http://www.broncosofficialonlinestore.com/Lamin_Barrow_Jersey_Broncos]http:... essential prerequisite for rational drug discovery and development. Our work elucidates sites of allosteric ligand binding on GPCRs and provides understanding of: interactions that govern both affinity and cooperative properties, modes of ligand binding, the potential for allosteric ligands to engender biased signalling and/or altered receptor regulation, and the identification of novel allosteric compounds as potential drug development leads. It is now recognised that this classical notion of intrinsic efficacy as an invariant constant cannot be correct. The most compelling data that have driven this conceptual shift involve drugs that, despite acting at the same receptor and in the same cellular background, differentially activate certain subsets of intracellular signalling pathways to the relative exclusion of others. desensitisation, phosphorylation, internalization), thus opening new vistas for achieving selectivity in "sculpting" cellular responses for therapeutic benefit. We are actively working to understand the broad spectrum of drug behaviour, how differential signalling profiles are engendered at a structural level and also whether we can predict ligand receptor behaviour based on knowledge of specific, molecular, ligand receptor interactions.