Integrated Drug Design For A New Generation Of Adrenergic Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$406,242.00
Summary
Fundamental to our ability to respond to both immediate and long-term environmental changes and stresses is the coordinated regulation of cellular functions by hormonal and neurotransmitter stimuli. The great majority of such stimuli are sensed by complex glycoprotein receptors on the surface of most cells that selectively bind and are activated by various hormones and neurotransmitters. Although there are several hundred distinct, but structurally related receptors of this kind, including the a ....Fundamental to our ability to respond to both immediate and long-term environmental changes and stresses is the coordinated regulation of cellular functions by hormonal and neurotransmitter stimuli. The great majority of such stimuli are sensed by complex glycoprotein receptors on the surface of most cells that selectively bind and are activated by various hormones and neurotransmitters. Although there are several hundred distinct, but structurally related receptors of this kind, including the adrenergic receptors (ARs), the molecular mechanisms involved in their activation and, thus, their regulation of vital cellular functions, remain unclear. Based on insights that we have gained from the development and characterisation of several mutated ARs, we have developed a model of receptor activation. In this application we propose to further test and extend the hypotheses underlying this model. Importantly, the functions regulated by ARs include vital responses, such as the maintenance of blood pressure by augmenting heart pump function and by constricting vascular smooth muscle. In addition, disordered cellular regulation by ARs has been implicated in a wide variety of diseases, including high blood pressure, congestive heart failure and enlargement of the heart. Thus, the studies detailed here to further understand the molecular mechanisms of receptor activation have broad implications for our knowledge of critical physiological control systems, and may lead to novel therapeutic approaches to treat a variety of diseases, including also tumours of the adrenal gland that cause excess adrenaline secretion. The cost and length of time associated with the development of a new drug in the pharmaceutical industry are enormous, and thus many promising medicinal agents never make it to the market. We propose to contribute to the drug discovery effort by developing novel combined methods for computer-aided drug design, to allow more efficient drug development.Read moreRead less
Biology Of EGFR Mutations In Glioblastoma Multiforme
Funder
National Health and Medical Research Council
Funding Amount
$287,445.00
Summary
The epidermal growth factor receptor (EGFR) is a protein that has a critical role in the development of normal cells. In glioma, the most lethal of the brain cancers, the EGFR is altered. These alterations result in uncontrolled activation of the EGFR, causing signals that promote the growth and survival of brain cancer. This grant seeks to understand the nature of the signals mediated by the altered EGFR, in turn helping us develop better therapeutics for the treatment of this deadly cancer.
Role Of Extracellular Surface Residues In Agonist Activation Of The Alpha1 Adrenoceptor
Funder
National Health and Medical Research Council
Funding Amount
$414,786.00
Summary
Most modern drugs act on a class of cellular proteins known as GPCRs. Despite their importance, little is known about how agonists acting from the outside of cells produce a change in GPCR structure allowing signalling to the cell's interior. We have identified new residues on the extracellular surface of the alpha1 adrenoceptor that dramatically affect agonist responses, opening the door to understanding the molecular process of GPCR activation and the development of drugs that can target diffe ....Most modern drugs act on a class of cellular proteins known as GPCRs. Despite their importance, little is known about how agonists acting from the outside of cells produce a change in GPCR structure allowing signalling to the cell's interior. We have identified new residues on the extracellular surface of the alpha1 adrenoceptor that dramatically affect agonist responses, opening the door to understanding the molecular process of GPCR activation and the development of drugs that can target different GPCR conformations.Read moreRead less