How Do Anaesthetics Work? A Rational Basis For Safer General Anaesthesia.
Funder
National Health and Medical Research Council
Funding Amount
$592,008.00
Summary
General anaesthetics are a mainstay of modern medicine, but have a small safety margin, requiring skilled anaesthetists for their safe use. There is growing evidence that general anaesthetic exposure may have long-term effects on brain function in both newborns and the elderly. This project will provide a detailed molecular description of anaesthetic action and specificity. It will provide the basis for designing new anaesthetics that are safer, both immediately and for long-term brain function.
Discovery Early Career Researcher Award - Grant ID: DE140100550
Funder
Australian Research Council
Funding Amount
$358,248.00
Summary
Quantum refinement of DNA X-ray structures. DNA carries the genetic map of life and refinement of its x-ray structures is a key tool to understand its functions. Standard refinement, however, relies strongly on empirical geometry constraints, and it is known that these can induce unphysical features. Quantum mechanical (QM) methods have now evolved to a level that offers an intriguing way out of this dilemma. In this project, state-of-the-art QM methods will be applied to DNA x-ray structures, a ....Quantum refinement of DNA X-ray structures. DNA carries the genetic map of life and refinement of its x-ray structures is a key tool to understand its functions. Standard refinement, however, relies strongly on empirical geometry constraints, and it is known that these can induce unphysical features. Quantum mechanical (QM) methods have now evolved to a level that offers an intriguing way out of this dilemma. In this project, state-of-the-art QM methods will be applied to DNA x-ray structures, and a unique quantum refinement scheme will be developed. Such a scheme will provide crystallographers with a new tool to determine DNA structures with greater accuracy and it will offer benefits to many areas of the life sciences that depend on such accurate structures.Read moreRead less
Computational enzymology: exploring the free energy landscape of enzymatic catalysis. Most biochemical reactions depend on enzyme catalysis and understanding how enzymes work at the molecular level remains a central question. This project will develop a suite of computational models to study the mechanisms of enzyme-catalysed reactions and such knowledge holds promise for technological benefits in the form of new drugs and novel catalysts.
Venoms To Drugs: Characterizing The Molecular Interactions Between Venom Peptides And Ion Channels With A View To Rational Drug Design
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
The conventional approach to drug development is reaching a state of crisis as it is producing fewer new drugs at increasing cost. A promising alternative is to harness the rich and diverse chemistry of venom peptides. This project aims to understand the mechanism by which venom peptides achieve their pharmacological activity. This knowledge is essential for venom-based drug design for treating diseases ranging from nervous systems disorders, stroke, chronic pain and psychiatric illnesses.
Engineering new tools to aid structure determination of membrane proteins. This project aims to address the inherent instability of G protein-coupled receptors (GPCRs), which are cell-surface proteins that are a major drug targets. The instability of GPCRs has resulted in a lack of atomic-level structural information that has hindered structure-based drug discovery efforts. This project expects to develop tools to improve GPCR stability and streamline the structure determination process. Project ....Engineering new tools to aid structure determination of membrane proteins. This project aims to address the inherent instability of G protein-coupled receptors (GPCRs), which are cell-surface proteins that are a major drug targets. The instability of GPCRs has resulted in a lack of atomic-level structural information that has hindered structure-based drug discovery efforts. This project expects to develop tools to improve GPCR stability and streamline the structure determination process. Project outcomes are intended to lead to significant advances in membrane protein structure determination and will have a substantial impact on future research in the pharmaceutical industry.Read moreRead less
Structural Biology Of Bacterial Lipid II-glycopeptide Antibiotic Interactions
Funder
National Health and Medical Research Council
Funding Amount
$605,190.00
Summary
Drug resistant bacteria are threatening our ability to successfully treat serious life-endangering infections, with many common antibiotics no longer effective. We will study in atomic detail how one class of antibiotics interacts with bacteria in order to design new members of this group that can overcome resistance.
Understanding sub-cellular systems at the atomic level. By extending the range of biomolecular systems that can be modelled computationally at the atomic level the project will enable important biomedical processes such as how bacterial toxins penetrate cell membranes and how protein hormones transmit signals into cells to be understood in unprecedented detail.
Force Fields for Structure Refinement and Computational Drug Design. The ability to model molecular systems at an atomic level, as used in protein structure refinement or computational drug design, is critically dependent on the accuracy with which inter-atomic interactions are represented. Highly optimised and well-validated interaction parameters are available for common biomolecules, such as amino acids, sugars and lipids, but not for co-factors, substrates and potential drug molecules, or ot ....Force Fields for Structure Refinement and Computational Drug Design. The ability to model molecular systems at an atomic level, as used in protein structure refinement or computational drug design, is critically dependent on the accuracy with which inter-atomic interactions are represented. Highly optimised and well-validated interaction parameters are available for common biomolecules, such as amino acids, sugars and lipids, but not for co-factors, substrates and potential drug molecules, or other molecules of interest such as polymers and dendrimers. The aim of this project is to develop and validate geometric and interaction parameters (force fields) for complex organic molecules and use these to facilitate bio-molecular structure refinement and computational drug design.Read moreRead less
Improving empirical force fields: a big-data approach. This project aims to improve the ability to represent the thermodynamic properties of molecules of biological, pharmaceutical or materials interest by developing force fields capable of describing a diverse range of molecules both consistently and with high fidelity. The project aims to exploit a rapidly expanding, in-house database of parameterized molecular structures to develop highly optimised, well-validated parameters that are both con ....Improving empirical force fields: a big-data approach. This project aims to improve the ability to represent the thermodynamic properties of molecules of biological, pharmaceutical or materials interest by developing force fields capable of describing a diverse range of molecules both consistently and with high fidelity. The project aims to exploit a rapidly expanding, in-house database of parameterized molecular structures to develop highly optimised, well-validated parameters that are both consistent and transferable, enabling molecules of any size or complexity to be parameterised with a fidelity currently only possible for simple organics. This will provide significant benefits, such as helping to improve the accuracy and reliability of ligand: protein complexes determined experimentally, a limiting factor in computational drug design.Read moreRead less
Theoretical modelling and design of safe covalent anti-cancer drugs. Covalent drugs are a new class of drugs with outstanding potential in cancer therapy. Detailed computer modelling studies will be performed to determine how these drugs interact with an important target in cancer therapy, the epithelial growth factor receptor, and thereby aid the development of new cancer treatments.