Themes

Drug Discovery Biology
Medicinal Chemistry
Centre for Drug Candidate Optimisation
- CDCO Platform
- CDCO Academic Node
Drug Delivery Disposition and Dynamics
Centre for Medicine Use and Safety

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Drug Discovery Biology
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Molecular & Translational Drug Discovery
Our research

Our research

To drive innovation, our lab integrates a broad spectrum of techniques and collaborations with world-leading partners.

This includes:

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🔬 Cryo-EM-supported structural biology for GPCR drug discovery View

Cryo-electron microscopy (CryoEM) has revolutionized GPCR drug discovery by enabling high-resolution structural characterization of these complex membrane proteins in near-native states. Unlike traditional X-ray crystallography, CryoEM allows the study of GPCRs in various conformations, including active and ligand-bound states, providing critical insights into their dynamic behavior.

We use this structural information to enhance drug discovery by facilitating the rational design of selective ligands, optimising drug-receptor interactions, and uncovering allosteric binding sites. We favour CryoEM as it is particularly valuable for GPCRs that are difficult to crystallise, accelerating the development of novel therapeutics targeting these key receptors.

We collaborate with the Center for CryoEM of Membrane Proteins (CCeMMP) utilising both their imaging infrastructure and membrane protein biochemistry expertise to enable CryoEM of traditionally difficult GPCRs including extensive work with orphan GPCRs, where the endogenous ligand remains unknown including GPR88 and GPR52 as pictured below.

🧪 High-throughput screening View

With the Australian Translational Medicinal Chemistry Facility and the Monash Fragment platform

High-throughput screening (HTS) is a powerful drug discovery tool that enables the rapid testing of large compound libraries to identify potential drug candidates. Using automated systems, HTS assesses biochemical or cellular responses to thousands of compounds in parallel, making it particularly valuable for targeting complex receptors like GPCRs. We have screened GPCR targets using the Servier compound library, the MIPS compound library, and the WEHI National Drug Discovery Center compound library. Building from the established GPCR biochemistry expertise required by CryoEM we also have worked with the Monash Fragment Platform to perform DNA encoded library screens.

We also collaborate with the Australian Translational and Medicinal Chemistry Facility (ATMCF) to develop compounds from hit to lead optimisation to ensure we generate the desired target product profile for a particular indication.

🧬 Analytical and mechanistic pharmacology View

Analytical and mechanistic pharmacology play a crucial role in GPCR drug discovery by providing a detailed understanding of how compounds interact with receptors and influence signaling pathways.

We use analytical pharmacology, which focuses on quantifying drug-receptor interactions, characterising binding affinities, and assessing functional responses using techniques like radioligand binding assays and fluorescence-based biosensors to help discriminate and develop screening hits into lead-like compounds.

We also use mechanistic pharmacology, which investigates the molecular mechanisms driving GPCR signaling, including biased signaling, allosteric modulation, and receptor dynamics. By elucidating these pathways, we aim to design more selective and efficacious therapeutics with improved safety profiles.

Together, these approaches enable the rational optimisation of drug candidates, improving their potency, specificity, and therapeutic potential.

Native tissue pharmacology View

Using murine neuronal culture, and human iPSCs (capitalising on the Themes outstanding imaging facility)

Native tissue pharmacology, mouse neuronal cultures, and human induced pluripotent stem cells (hIPSCs) are essential tools for GPCR drug discovery, providing physiologically relevant models to assess drug effects in complex neuronal environments. Our lab has established several models to investigate native tissue pharmacology in neurons. This work enables the study of drug responses in intact neuronal circuits, preserving endogenous receptor expression, signaling complexity, and tissue-specific regulation, offering insights beyond traditional cell-based assays.

Mouse Neuronal Cultures provide a controlled, reproducible platform to study GPCR signaling, synaptic function, and drug effects in primary neurons, bridging the gap between in vitro and in vivo studies.
hIPSC-Derived Neurons offer a human-relevant model for drug testing, allowing us to study patient-specific neuronal responses, disease mechanisms, and potential personalized therapies.

Together, these approaches improve translational relevance, helping to refine and validate novel GPCR-targeting therapeutics before clinical application.

Representative immunofluorescence image of primary cortical neurons cultured from E15 mouse embryos, fixed at 14 days in vitro (DIV14). Neurons were stained with a combination of antibodies to visualise distinct cellular components: MAP2 (magenta): A dendritic marker highlighting the extensive and complex dendritic arborisation characteristic of mature neurons. TFEB (green): A transcription factor associated with lysosomal biogenesis and autophagy, visible in discrete puncta throughout the cytoplasm and possibly within the nucleus. LAMP1 (red): A lysosomal marker delineating the lysosomal compartments within neuronal soma and processes. DAPI (blue): A nuclear stain marking DNA, used to identify the nuclei of both neurons and any non-neuronal cells present in the culture. This multichannel fluorescent image provides a comprehensive view of neuronal morphology, subcellular localisation of TFEB, and the distribution of lysosomes in a mature neuronal network. Imaging and analysis by Sanja Bosnyak-Gladovic.

Human stem cell-derived neurons and astrocytes (FujiFilm GlutaNeurons and iAstrocytes) were immunolabeled for MAP2 (cyan) to visualize neuronal cell bodies and dendrites, GFAP (magenta) to label the astrocyte cytoskeleton, and Synapsin (yellow) to mark presynaptic terminals. Nuclei were counterstained with DAPI (dark blue). Imaging and analysis by Holly Melland

Human induced pluripotent stem cell-derived neurons (NGN2) after 20 days in culture were immunolabeled for Beta III Tubulin (green) to visualise the neuronal cytoskeleton, MAP2 (red) to label neuronal cell bodies and dendrites, and DAPI (blue) to stain nuclei. Imaging and analysis by Holly Melland

🐭 Rodent models of disease View

In collaboration with the Florey Institute

Rodent models that reliably mimic the human condition remain a persistent challenge in psychiatry drug discovery. In collaboration with A/Prof Jess Nithianantharajah and her team at The Florey, we are continually developing new methods to aid in development of new pharmacological tools and novel compounds that can then progress deep into preclinical development. The cornerstone of this work is using touchscreen-based cognitive assays, adapted from human neuropsychological tests, to provide a translational approach to assessing cognitive and behavioral functions in rodents. Using pharmacological interventions we can model specific aspects of disease and derive clinically-relevant endpoints that also align with endpoints from clinical trials. Combining rodent disease models with touchscreen assays enhances the predictive validity of drug candidates, facilitating the development of more effective and targeted treatments.

For further information, please contact Greg Stewart or Natalie Diepenhorst.

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Our team
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Monash Institute of Pharmaceutical Sciences

Monash Institute of Pharmaceutical Sciences

Our research

🔬 Cryo-EM-supported structural biology for GPCR drug discovery View

🧪 High-throughput screening View

🧬 Analytical and mechanistic pharmacology View

Native tissue pharmacology View

🐭 Rodent models of disease View

Learn more

Our team

Publications

Alumni

In the news

Collaborators