The 2022 FBDD DU Conference proved to be a huge success for CFBD members. We heard fantastic presentations from the plenary speakers and fascinating stories from the presenters with a good number of Centre members represented. We saw brilliant posters and made new connections during the networking sessions. Adding to this, our members hit the jackpot with the FBDD DU presentation prizes. Congratulations to:
FBDD Down Under 2022 excites with a stellar speaker line-up: A/Prof Charlene Kahler from The University of Western Australia, Dr Chris Smith FRSC from Mirati Therapeutics, Dr Jan Wollenhaupt from Helmholtz-Zentrum Berlin, Dr Ben Davis from Vernalis, Dr Anders Friberg from NUVISAN GmbH and Dr Olga Ilyichova from Monash University and ANSTO. Don’t forget to register: https://fbdddownunder.com.au/registration/
Good news! The abstract submission deadline for the 4th FBDD Down Under Conference will be extended to 29 July 2022.
Important Dates:
Abstract submission deadline oral presentation – 29 July 2022
Abstract submission deadline posters – 12 August 2022
Conference dinner – 28 September 2022
Registration close – 14 September 2022 (5 pm AEST)
The conference will include workshops, scientific sessions and social events. For more details, please visit the FBDD DU website.
Do you want to support this event? We offer a variety of sponsorship packages to help you promote your technology. Contact us to discuss the different options on offer.
We have a postdoctoral position available for a Biomolecular NMR spectroscopist/Structural Biologist within the ARC Centre for Fragment-Based Design.
The exciting opportunity for a Research Fellow who will be working our Centre. The successful candidate will contribute to research on fragment-based drug design projects with a focus on a range of therapeutic targets across different areas such as infectious disease, cancer and diabetes.
You will have:
If you are ready to take the next step in your research career, we look forward to receiving your application.
Congratulations to PhD student Karoline Sanches from Monash University who published a paper as first author. The paper was published in Toxicon in October 2021.
Karoline Sanchesa,b,1, Dorothy C.C. Waia,1, Raymond S. Nortona,b
aMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia
bARC Centre for Fragment-Based Design, Monash University, Parkville, Victoria, 3052, Australia
1These authors contributed equally
Peptide toxins are often potent and selective blockers of ion channels and are therefore of significant interest to the pharmaceutical and biotech industries. For example, an analogue of the sea anemone peptide ShK, which targets the voltage-gated potassium channel Kv1.3, is currently in clinical trials for the treatment of autoimmune disorders. Studying the structure-function relationship and the dynamics of these peptides is pivotal to understanding their binding to receptors, as well as to designing new drugs. In this article, we highlight the important contribution of NMR to characterising peptide toxin dynamics. It is shown that even disulphide-rich peptides display dynamics in various timescales, the characterisation of which through NMR is crucial for understanding their receptor interactions.
CFBD CI Professor Ray Norton has been awarded a grant worth $49,000 from the Monash Health Foundation 65 km Walk for Cystic Fibrosis Research Funding for his project entitled “Validating a potential new target for the treatment of cystic fibrosis”.
Ray’s project seeks to determine whether the protein channel KV1.3 plays a role in airway inflammation in individuals with cystic fibrosis [CF]. Ray and his team will examine broncho-alveolar lavage [BAL] fluid obtained from both young children with CF and adults with CF following lung transplantation.
Previous research has shown that KV1.3 is involved in other inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, but it is unknown if it is also important in CF lung disease or rejection in CF lung transplant recipients.
Lung inflammatory cells from BAL fluid will be tested for the presence of the KV1.3 channel. The group will also analyse BAL fluid from adults with CF post lung transplant, who will be having BAL as part of their routine post-transplant care at the Alfred Hospital Lung Transplant Service. We expect to find that KV1.3 is abundantly present in airway inflammatory cells in both patient groups.
If KV1.3 is detected, the next step will be to test whether blocking this channel with HsTX1[R14A], a novel peptide developed at Monash University, reduces inflammation and lung damage in animal models of CF lung disease and chronic rejection.
The ARC CFBD aims to advance the techniques and workflows of fragment-based drug design to establish new avenues for drug discovery. Our team have used our novel workflow called REFiL (Rapid Elaboration of Fragments into Leads) to demonstrate accelerated development of leads for drug discovery. This new method has the potential to produce a drastic reduction in cost for R&D, as well as expedite identification of potential drug leads.
Fragment-Based Drug Discovery (FBDD) is an established field of study where small drug building blocks of less than 20 non-hydrogen atoms (i.e. fragments) form the basis for lead-like compounds. Fragment-based leads are superior candidates for progressing through to drug development because they offer opportunities to incorporate better physical properties and, therefore, tackles the issue of late stage attrition that can occur in traditional drug discovery pipelines.
Despite these advantages, FBDD is not without its drawbacks. Elaboration of fragments into potent leads typically relies on structural data, usually in the form of X-ray crystallography, which is a costly bottleneck and limits the type of protein targets to those that readily crystallise. Generation of various elaborated compounds to test for potency is also inherently expensive and time-consuming – rendered more laborious by the need for compound purification. Unfortunately, it is often the case that these elaborated compounds achieve meagre affinity gains that fail to justify the cost of consumables for synthesis or purification.
Our REFiL workflow aimed to address these hurdles. First, our program of analogue design leverages chemical diversity in lieu of structural data to guide compound generation. Second, this chemistry is performed in parallel, on microscale and in a plate-based format using curated reagent libraries, making this highly cost- and time-efficient. These elaborated libraries can then be assessed unpurified using Off-Rate Screening by SPR. This ability to generate huge amounts of chemical matter which could be assessed unpurified drastically expedited this traditionally laborious process. The workflow boasts an impressive 100-fold affinity improvement in the space of under a year to achieve lead-like compounds.
Published on ChemRxiv, the team applied the REFiL workflow to develop lead-like compounds for the extra terminal domain of bromodomain-3 (BRD3-ET), a target for cancer therapeutics. Bromodomain containing proteins are key regulators of transcription in the cell cycle, and the oncological potential of these proteins is well established.
The application of REFiL to BRD-3ET led to three promising analogues for further development into lead-like compounds. On a target specific level, this represents a huge step in the fields of oncology and epigenetics as the role of the extra terminal domain is poorly elucidated. Designing lead-like compounds for BRD-3ET will help illuminate the holistic function of this protein in transcriptional activity.
The impact of this workflow has widespread application potential throughout the pharmaceutical industry. It could see a reduction in R&D costs from failed early stage candidates. More topically, the cheap and expedited nature of lead generation by REFiL is sorely needed in tackling COVID-19 and other poorly understood diseases. We stand to greatly fine-tune our understanding of disease with the generalised application of this workflow.
Rapid elaboration of fragments into leads applied to Bromodomain-3 extra terminal domain
Adams, L. A.; Wilkinson-White, L. E.; Gunzburg, M. J.; Headey, S. J.; Scanlon, M. J.; Capuano, B.; Mackay, J. P.; Doak, B. C.
ARC Centre for Fragment-Based Design 