Research areas
Medicinal chemistry is both fundamentally focused and translational. Our research is completed in a multidisciplinary, iterative feedback cycle of design, synthesis and biological testing. The objective is to optimise the potency, selectivity and bioavailability of a compound, while minimising side effects.
Anti-cancer medicinal chemistry
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The term "cancer" refers to a group of diseases that involve abnormal cell growth with the potential to spread to other parts of the body. As each cancer consists of a variety of different cell types highly effective at developing resistance to both drug and radiation therapy, it is a particularly difficult disease to treat. The challenge for the field of medicinal chemistry is to design drugs capable of selectively targeting cancer cells while avoiding multidrug resistance pathways.
Using recent insights into the unique attributes of cancer cells, Medicinal Chemistry is pursuing anti-tumour agents of high specificity to help design suitably targeted, selective chemotherapeutics. Current programs involve a diverse array of anti-cancer targets, such as lipid and protein kinases, microtubules, topoisomerases, hypoxia inducible factors, bromodomains and histone acetyltransferases.
Drug discovery approaches include:
- optimisation of screening hits using structure-activity relationship-guided and in silico techniques
- synthesis and optimisation of anticancer natural products
- bioconjugation of active agents to cancer seeking biomolecules
These approaches are complemented by research into new synthetic methods for expediting lead optimisation, drug-biomolecule conjugation and asymmetric natural product synthesis. These programs are undertaken in collaboration with other researchers at MIPS and other cancer research institutes in Australia and abroad.
Research groups
Infectious diseases
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The world is facing an enormous and growing threat from the emergence of superbugs that are resistant to most currently available antibiotics. Medicinal Chemistry researchers are collaborating on multiple programs to discover the next generation of antibiotic agents.
Anti-infective agents
We employ fragment-based drug design to identify and curate novel compound libraries that target non-essential microbial functions without inhibiting growth. This tactic has the potential to develop new anti-infective agents that will not exert strong selection for resistance. Our focus in this area are on Mycobacterium tuberculosis and human immunodeficiency virus (HIV).
Peptide antibiotics
We collaborate with Drug Delivery, Disposition and Dynamics to enhance the therapeutic use of polymyxin antibiotics. We developed refined synthetic methods enabling the synthesis of more than 400 variants of this cyclic lipopeptide, allowing us to identify the molecular determinants of antibacterial activity, as well as kidney toxicity—the major dose-limiting side effect of these antibiotics.
Antimalarial agents
Malaria is the world's most prevalent parasitic disease. The spread of drug-resistant parasites has rendered most of the current antimalarial treatments ineffective. We are developing next generation antimalarial agents with novel modes of action using fragment-based drug discovery and structure-based drug design approaches.
Human African trypanosomiasis (HAT) and Chagas disease
HAT, more commonly known as sleeping disease, and Chagas disease are parasitic infections affecting tens of thousands to millions of people. While these diseases have significant medical and socioeconomic impact, the treatment options for both are limited. We are developing drug lead compounds to treat these neglected diseases through a series of structure-activity relationship studies.
Research groups
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Flynn Group
Our research improve drug-discovery outcomes by enhancing our capacity to modify molecular structure in response to key-performance criteria
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Norton Group
Our group employs a range of biophysical approaches, molecular modelling and design in studies of peptides and proteins from venomous organisms
Chemical biology
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Chemical biology seeks to unravel the causes of diseases and identify crucial biological targets for disease treatment and prevention. We alsoapply chemical principles to the modification of native biological molecules to create new function. Our researchers in this area are therefore heavily involved in the development of new medical diagnostic agents, drug delivery systems and screening assays.
A major focus is the development of probes to explore the pharmacology of G protein-coupled receptors (GPCRs), including fluorescent ligands that enable the localisation, trafficking and signalling mechanisms of GPCRs to be studied in live cells via advanced fluorescence microscopy techniques.
We are also developing a wide range of novel 'tagging' reagents to label biomolecules with luminescent dyes, radioactive metal complexes, spin labels, paramagnetic tags, and a variety of other detectable moieties. These are being employed in conjunction with sophisticated new bioconjugation methodologies and analytical techniques—to study the structure and function of potential new drug targets and develop new medical diagnostics and therapeutic agents.
Research groups
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Capuano Group
Our group specialises in the design, synthesis and biological evaluation of ligands targeting proteins implicated in mental health disorders and cancer
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Flynn Group
Our research improve drug-discovery outcomes by enhancing our capacity to modify molecular structure in response to key-performance criteria
G protein-coupled receptor drug discovery
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G protein-coupled receptors (GPCRs) are the target of approximately 30% of currently marketed drugs, so understanding their molecular functionality is both clinically and commercially relevant.
The recent clarification of the X-ray and cryogenic electron microscopy structure of GPCRs has opened new research opportunities, which we're strongly pursuing with our Drug Discovery Biology colleagues.
In addition to traditional medicinal chemistry programs around GPCR drug discovery, we work in frontier areas such as allosteric modulators of GPCRs, as well as bitopic and bivalent ligands. The adenosine, dopamine, muscarinic acetylcholine and sphingosine-1-phosphate receptors are the focus of these studies.
Research groups
Peptide science
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We have core expertise in the area of peptide science. This encompasses the design and generation of bioactive peptides and peptidomimetics, structural studies of peptides by NMR and computer modelling, and generation of peptide conjugates for imaging or novel delivery systems.
Peptides constitute a fruitful starting point for developing therapeutic and diagnostic agents. Among our lead peptides are natural product toxins from scorpions and sea anemone species and bacteria. Equally, we can adapt human peptide hormones, modifying their native biological behaviour for pharmacological applications.
Peptides have potent physiological effects, but often their use as therapeutics is limited by poor in vivo stability and hindered transport across biological barriers. Modifying peptides structurally can overcome these limitations and lead to effective treatments. In addition, conjugation of peptides with other groups can provide for diagnostic labelling or enhanced drug delivery properties.