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Brain Research, which has unique expertise in growing cells from donated human brain tissue into living drug test systems. Alongside the in-vitro testing, the project brings together a complete pipeline of specialists to bring treatments to patients as quickly, safely and effectively as possible, including AI modelling expertise from the Auckland Bioengineering Institute, led by Abbasi (with Research Assistant Shanan Chand), and clinical insight from doctors working directly with patients – all backed by the supercomputing power of the New Zealand eScience Infrastructure (NeSI). “When you put it all together, this patient-centred drug discovery process is something that has not been seen before in New Zealand or worldwide,” Flanagan says. “We’re not just theorising. We are combining global advances in chemistry, national supercomputing infrastructure, AI, real human brain tissue donated by New Zealanders, and clinical need, tomove potential treatments closer to reality. “It’s really important to us that New Zealanders are at the front of this pipeline, choosing the molecules that work for us. That is why the taonga of donated human tissue and the Hugh Green Biobank is so important in our work.” By the end of the three-year programme, the team aims to take the most promising leads to pre-clinical trials and start the next phase of progressing treatments to patients. As part of that vision, the teamwants to enable other researchers to use their model of patient-centred molecular discovery technology, enhancing the New Zealand neuroscience research landscape and moving knowledge of brain disease into future drug discovery. Lessons from oncology Part of the inspiration for the programme came from what Flanagan and Dragunow had seen taking place in developing cancer treatments. “In oncology, we’ve been designing drugs to target specific enzymes inside cancer cells that control how they grow, divide and respond to their environment,” Flanagan says. “That gave us the idea that we could use those same cancer drugs to learn more about how brain cells control neuroinflammation.” They tested this idea by screening compounds known to target cancer pathways in brain-cell models of neuroinflammation. This identified the involvement of a class of enzymes called cyclin-dependent kinases. Some of the enzymes in this family have long been studied in cancer research, with some emerging research showing effects in inflammation. The team focused in on one of these enzymes, applying NeSI’s supercomputing power to complete a digital screen of a library of 118 million molecules against the enzyme’s 3D atomic structure. The screen took two weeks to complete and delivered hundreds of candidates with the potential to turn off the enzyme in brain cells. Then, by testing fewer than 100 of these against patient-derived brain cells, the researchers identified one that was able to block an inflammatory response. This validated the idea and created a foundation for the new Drug Discovery Programme to take shape. While this is a significant head start, there are potentially thousands of other enzymes or proteins involved in neuroinflammation that we do not know about. Conole, a chemical biologist at the University of Auckland Cancer Society Research Centre, adds his expertise to illuminate what he calls the “dark matter” in brain cells. Flanagan leads a new $1MDrug Discovery Programme, supported by a team of exceptional University of Auckland scientists – Professor Mike Dragunow, Dr Daniel Conole and Dr Hamid Abbasi. The programme utilises advances in supercomputing and artificial intelligence (AI) to screen hundreds of millions, even billions, of molecules. Known as ultra-large- scale drug screening, it is changing howwe tackle brain disease in New Zealand. “Such massive scale creates the compelling idea, that hidden among those billions of molecules is one, the one molecule, that will successfully navigate the drug development process and actually do the job of getting into the brain and treating neuroinflammation,” Flanagan says. Neuroinflammation is a process where cells of the immune system attack healthy brain cells, contributing to the development and progression of many brain disorders including Alzheimer’s, Parkinson’s, epilepsy, stroke and concussion. It was chosen as the target for the programme as there is a huge lack of treatments for neuroinflammation, and it is implicated in so many brain diseases. The team is building on an existing ‘library’ of hundreds of millions of molecules screened with early support from the Hugh Green Foundation – who will help to co-fund this next phase of research. Since the new drug discovery programme got underway in late 2025 it very quickly cracked the 700 million molecule mark. “Our target of one billion is already very, very close,” Flanagan says. At the heart of the project is a technique known as molecular docking – using computers to predict howwell a potential drug molecule might bind to, and turn off, a target protein involved in disease. “Molecular docking simulates the interactions between a potential drug molecule and a target protein using their three‑dimensional structures, at the atom level. We then look for molecules that make the interactions required for an effective drug.” The next planned stage is to test the most promising compounds directly on human brain cells and tissues. “These are the exact cells and tissues that a neuroinflammation drug needs to act on, so bringing them to the forefront of our discovery will accelerate our progress to real-world treatments.” This in-vitro (outside of a living organism) testing takes place at the Hugh Green Biobank at the Centre for Daniel and Jack with Professor Mike Dragunow (centre) at the University of Auckland. “We’re not just theorising. We are combining global advances in chemistry, national supercomputing infrastructure, AI, real human brain tissue donated by New Zealanders, and clinical need, to move potential treatments closer to reality.” Associate Professor Jack Flanagan “It’s exhilarating to think how quickly we could move from a billion molecules to finding one that could be developed into a drug.” Associate Professor Jack Flanagan Professor Mike Dragunow (photo credit - Media Productions University of Auckland) 12 Headlines 13 Headlines