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
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
Role Of Conformational Change In Activation Of The Growth Hormone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This project seeks to find out how growth hormone sends its signal into the target cell through its surface receptor. It is believed that ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This project seeks to find out how growth hormone sends its signal into the target cell through its surface receptor. It is believed that the primary event in signalling is the ability of the hormone to bring two receptors together (receptor dimerization). However, it may be that the receptor already is dimerized, and the role of the hormone is to induce a specific change in shape of the receptor, which transfers the signal of hormone binding into the cell to initiate signalling to the genome. We have good evidence that a specific shape change is required for activation of an important signalling pathway by growth hormone, and the closely structurally related receptor for erythropoietin is already dimerized before hormone binds. We want to find out exactly how the shape change acts, and whether the receptor is predimerized. This information is vital for designing small orally active mimics of growth hormone which could be of great value as an anabolic supplement for the frail elderly.Read moreRead less
Tropisetron: Molecular Mechanisms Of Action At The 5-HT3 Receptor And The Glycine Receptor
Funder
National Health and Medical Research Council
Funding Amount
$371,800.00
Summary
Tropisetron and related drugs are used clinically to combat chemotherapy-induced nausea and vomiting. These drugs are termed '5-HT3 antagonists' because they block the activity of 5-HT3 receptor ion channels, which are found in parts of the brain that control the vomit reflex. Tropisetron also has potent effects on the glycine receptor chloride channel, which inhibits the nervous system. Depending on the concentration used, tropisetron can either increase or decrease the activity of the glycine ....Tropisetron and related drugs are used clinically to combat chemotherapy-induced nausea and vomiting. These drugs are termed '5-HT3 antagonists' because they block the activity of 5-HT3 receptor ion channels, which are found in parts of the brain that control the vomit reflex. Tropisetron also has potent effects on the glycine receptor chloride channel, which inhibits the nervous system. Depending on the concentration used, tropisetron can either increase or decrease the activity of the glycine receptor. If a drug can be found to selectively increase glycine receptor activity, it may be useful as an analgesic. In this project, we aim to understand the molecular mechanisms by which tropisetron interacts with the 5-HT3 receptor and the glycine receptor. This may help to identify novel analgesic drugs and more selective anti-emetic drugs.Read moreRead less