CFBD researchers are again invited to apply for a CFBD Travel Grant to the value of up to $3,500. This grant may be used for travel to a national or international conference, a visit to a partner organisation for research collaboration or a visit to a research laboratory to learn a new technique. The CFBD TravelGrant is an annual award.
Applications are open from 20 March to 21 April 2023 (COB). Please refer to the Eligibility Criteria and Application Form for further details.
CFBD members Karol Sanches, Yildiz Tasdan and Jack Phelps (all Monash) have started their international placements as part of their ARC scholarships. While Karol has already completed her placement with TetraGenetics in Boston (USA), Yildiz and Jack are working at Vernalis in the UK. Here, Jack talks about his experience during his first couple of weeks:
“How time flies! It still feels like yesterday that I was saying goodbye to Melbourne and flying home to the UK to start my placement at Vernalis, Cambridge. I’ve now somehow been here for 3 months and am loving the experience of working in the industry. Of course, there are similarities (every day starts with coffee before setting up experiments), but also many notable differences. As expected (but slightly annoyingly) there’s a real sense that money, not discoveries themselves, is the driving force behind each project here, and when talking about my work it’s difficult to describe the end goal in terms of industry buyouts (which feels a long way off yet!). On a more personal note, the most exciting difference for me is on the technology side: All the columns are automatic and can be monitored remotely from your desk! Luckily, this is the case in protein purification too, as I’ve become much more of a biologist over the past couple of months. This brings me to the other major new experience in industry – not having to make up LB or wash/autoclave your own glassware! Call it laziness if you’d like, but I prefer to think of it as more time to spend doing the science… As well as protein science, I’ve also been fortunate enough to model protein sequences using AlphaFold and to start exploring crystallography.
All this being said though, I’m still missing the people at MIPS that kept me going during my PhD. With all the new helpful technicians and processes, there’s no substitute for the community of students and the city of Melbourne.”, Jack Phelps (Monash)
We will post more updates from Karol and Yildiz soon. Stay tuned!
We are proud to sponsor the 2022 ANZMAG Conference this year. The event will take place in Marysville, VIC from 4 to 8 December. CFBD is sponsoring one of the keynote speakers A/Prof Haribabu Arthanari from Harvard Medical School. Register to hear fascinating talks about all things #magneticresonance
Please visit https://www.anzmagconference.org.au/ for more information and registration details.
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:
Another round of the CFBD Seminar Series is coming on 29 August 2022: Prof Marko Hyvönen will talk about the development of inhibitors for BRCA2:RAD51 interaction.
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/
This month, we are welcoming Dr Jing Dong from Astex Pharmaceuticals as a speaker at our CFBD Seminar Series.
The next Fragment-Based Drug Design Down Under Conference will be held at Monash Parkville Campus, Melbourne from 28 to 30 September 2022.
The conference will include workshops, scientific sessions and social events. There will be poster and oral presentation prizes for student and ECR delegates.
Topics to be covered are library design, fragment screening, structural biology, computation chemistry, fragment-to-hit-to-lead chemistry and success stories.
For more information, visit fbdddownunder.com.au.
Not one but five CFBD members from our three nodes published a paper on DsbA titled “Identification and characterization of two drug-like fragments that bind to the same cryptic binding pocket of Burkholderia pseudomallei DsbA” in Acta Crystallographica Section D.
Disulfide-bond-forming proteins (Dsbs) play a crucial role in the pathogenicity of many Gram-negative bacteria. Disulfide-bond-forming protein A (DsbA) catalyzes the formation of the disulfide bonds necessary for the activity and stability of multiple substrate proteins, including many virulence factors. Hence, DsbA is an attractive target for the development of new drugs to combat bacterial infections. Here, two fragments, bromophenoxy propanamide (1) and 4-methoxy-N-phenylbenzenesulfonamide (2), were identified that bind to DsbA from the pathogenic bacterium Burkholderia pseudomallei, the causative agent of melioidosis. The crystal structures of oxidized B. pseudomallei DsbA (termed BpsDsbA) co-crystallized with 1 or 2 show that both fragments bind to a hydrophobic pocket that is formed by a change in the side-chain orientation of Tyr110. This conformational change opens a `cryptic’ pocket that is not evident in the apoprotein structure. This binding location was supported by 2D-NMR studies, which identified a chemical shift perturbation of the Tyr110 backbone amide resonance of more than 0.05 p.p.m. upon the addition of 2 mM fragment 1 and of more than 0.04 p.p.m. upon the addition of 1 mM fragment 2. Although binding was detected by both X-ray crystallography and NMR, the binding affinity (Kd) for both fragments was low (above 2 mM), suggesting weak interactions with BpsDsbA. This conclusion is also supported by the crystal structure models, which ascribe partial occupancy to the ligands in the cryptic binding pocket. Small fragments such as 1 and 2 are not expected to have a high energetic binding affinity due to their relatively small surface area and the few functional groups that are available for intermolecular interactions. However, their simplicity makes them ideal for functionalization and optimization. The identification of the binding sites of 1 and 2 to BpsDsbA could provide a starting point for the development of more potent novel antimicrobial compounds that target DsbA and bacterial virulence.
Read the full article here.
Congratulations to PhD student Sarah Müller from Griffith University who published a paper as first author.
Most of the drugs we know target the activity of specific proteins that play an important role in the disease being treated. One of the big challenges in the discovery of new drugs is finding molecules that bind specifically to one target and not bind to other proteins too. This is necessary to avoid causing treatment side effects. Hence, drug discovery researchers are always on the lookout for ways to find better lead molecules.
We identified an old drug class called glitazones that target a new protein known as carbonic anhydrase II, an enzyme that helps to maintain pH levels in cells. Carbonic anhydrase comes in many different forms and has been a successful target for drug development for various diseases like glaucoma, heart failure and epilepsy.
The glitazone drugs, such as rosiglitazone, are used to treat Type II diabetes. However, because of the severe side effects caused by the use of glitazones they were taken off the market. Our findings suggest that the unintended targeting of carbonic anhydrase may be one reason for the side effects of these drugs. This shows how important it is to carry out research to fully understand the effect of drugs and can help future researchers in drug discovery.
The paper was published in Molecules in May 2021.
ARC Centre for Fragment-Based Design 