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The strategy of FBDD involves screening libraries of small chemical compounds or ‘fragments’ that, owing to their size, generally bind with relatively low affinity and then elaborating these to produce larger, higher affinity ligands (or hits). The process of fragment elaboration to generate high-affinity compounds remains one of the major challenges in FBDD. Projects in the CFBD involve research in different aspects of this process and require expertise in one or more of the following areas: medicinal chemistry, structural biology, biophysics, and/or biochemistry.
Current projects involve the development of novel antibacterial and antiviral compounds; development of novel approaches to screening “difficult” targets; development of compounds for the treatment of metabolic disease.
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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.
Dr Anitha Kopinathan was awarded an Early Career Researcher Grant by The Australian Institute of Nuclear Science and Engineering (AINSE).
AINSE boosts the capability of Australia and New Zealand in nuclear science, engineering and related research field by facilitating collaboration, education and training. The Early Career Researcher Grant provides a single payment of A$10,000 to contribute to expenses in travel, accommodation, consumables and carer requirements for the recipient.
Dr Kopinathan’s Early Career Researcher Grant will support her collaborative research with Australia’s Nuclear Science and Technology Organisation. She will synthesise 19F-13C labelled amino acid probes for the investigation of protein structure and dynamics by NMR spectroscopy. Incorporation of isotopically labelled amino acids into proteins improves the resolution of NMR signals, allowing larger biomolecular systems to be investigated.
Her work will benefit the research efforts of ARC CFBD in furthering our understanding of protein dynamics, ligand binding and the interplay between the two.
Dr Narelle Tunstall, Centre Manager
The Centre for Fragment-Based Design officially commenced on 22 July 2019 with the execution of our Participants Agreement and the Centre was launched by The Honourable Kevin Andrews MP on 12 November 2019. The launch was held in conjunction with Australia’s national conference on Fragment-Based Drug Design, which allowed us to leverage a full week of activities including our first Scientific Advisory Board meeting and the Centre’s first training events, in partnership with key industry and international stakeholders.
The launch, conference and training workshops were very well received by attendees, with many of our academic and industry participants and other stakeholders in attendance. These initial activities have established a strong base of interest in the Centre for further collaborative opportunities that will drive our research initiatives and support growth, productivity and competitiveness in fragment-based design for the sector.
There was some great coverage of the event. Monash and Griffith both had media releases publicising the launch event, which were picked up by a Universities to Business article.
Our partners GE Healthcare (now Cytiva) had a number of representatives, including Paul Belcher all the way from Boston, who wrote a great LinkedIn article about the event.
Dan Erlanson wrote a great summary article on his Practical Fragments blog.
Our objective to establish a coherent and collaborative national network to provide access to the technology necessary to support fragment screening against a wide range of protein targets, has now been firmly grounded in the established Centre. We now have a strong platform and clear means to implement our training program activities, accelerate research translation and continue to engage with industry to meet the growing needs within the rapidly moving sector.
Feature image: Centre CIs (L-R: Professor Jonathan Baell, Professor Sally-Ann Poulsen, Professor Michael Kassiou, Professor Joel Mackay, Dr Maria Halili, Professor Martin Scanlon and Professor Ray Norton) with ARC CEO Professor Sue Thomas and Centre Manager Dr Narelle Tunstall.
Latest research from the Centre, Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain, published in ChemRxiv, March 2020.
The research team use an integrated workflow for the Rapid Elaboration of Fragments into Leads (REFiL) that provides a systematic approach to generate higher-affinity binders without the need for structural information.
Adams, L. A., Wilkinson-White, L. E., Gunzburg, M. J., Headey, S. J., Scanlon, M. J., Capuano, B., Mackay, J. P., and Doak, B. C. Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain. ChemRxiv. 2020. 10.26434/chemrxiv.12026952
The research paper, The Fragment-Based Development of a Benzofuran Hit as a New Class of Escherichia coli DsbA Inhibitors, was published in Molecules, October 2019. The work takes a fragment-based drug discovery approach to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli (EcDsbA). It suggests the potential to develop benzofuran fragments into a novel class of EcDsbA inhibitors.
Duncan, L., Wang, G., Ilyichova, O. V., Scanlon, M. J., Heras, B. M., & Abbott, B. The Fragment-Based Development of a Benzofuran Hit as a New Class of Escherichia coli DsbA Inhibitors. Molecules 2019, 24(20), 3756. https://doi.org/10.3390/molecules24203756
New research, Peppy: A virtual reality environment for exploring the principles of polypeptide structure, published in Protein Science, 2020.
Joel Mackay (USYD) and collaborators built a virtual reality application, ‘Peppy’ aimed at facilitating teaching of the principles of protein secondary structure to undergraduate biochemistry students. Research findings on the implementation and use of Peppy, as well as outcomes of deploying Peppy in undergraduate biochemistry courses were first published in October 2019 in Protein Science.
The application is novel, dynamic and fun to use, allowing “exploration of the relative effects of hydrogen bonding, backbone φ/ψ angles, basic chemical structure, and steric effects on a polypeptide structure”.
Doak, D., Denyer, G., Gerrard, J., Mackay, J., Allison, J. Peppy: A Virtual Reality Environment For Exploring The Principles Of Polypeptide Structure. Protein Science. 2020. 29:157–168. https://doi.org/10.1002/pro.3752.
A HUGE congratulations to our very own Beatrice Chiew who is this years Monash 3MT winner and a Top 10 finalist of the 3MT Asia-Pacific final!
This is a fantastic achievement and we are incredibly proud of her, her research and her amazing sci-com skills!
Watch her Asia-Pacific final presentation here.
Martin Scanlon is the Director of the ARC CFBD and his research group is based at Monash Institute of Pharmaceutical Sciences (Parkville campus).
Members of the Scanlon group were dragged out of their labs and offices to update the group photo recently… we have a few openings in the back row… do you want to join us?
ARC Centre for Fragment-Based Design 