ACADEMIC RESEARCH • 學術研究 2022 UMAGAZINE 25 • 澳大新語 56 However, mitogenic inducers are currently scarce, and safe triggers are particularly lacking. Therefore, we need more effective ways to find such inducers and build a safer bank of drug candidates. At the University of Macau (UM), our team is working with the University of Oslo and Hangzhou Mindrank Technology Co Ltd to develop an artificial intelligence (AI)-based virtual screening algorithm that integrates molecular data in multiple dimensions. The algorithm and multi-species AD validation models for cell culture systems, nematodes, and mice have enabled us to identify several small-molecule compounds with therapeutic potential against AD. AI-assisted Identification of Mitophagy Inducers Over the years, our team at UM has worked on extracting natural small molecules from traditional Chinese medicine (TCM) as autophagy modulators. We have also conducted related pharmacological studies on biological activity and built a database of natural small molecules from different chemical classes, such as alkaloids, flavonoids and terpenoids. Our international cross-institutional partnership has led to the development of a machine learning model. The model was pre-trained on data from 19 million small molecules from the ChEMBL and ZINC databases. This representation model takes in molecular information of different dimensions. They include one-dimensional simplified molecular-input line-entry system (SMILES) sequence information, two-dimensional molecular topological similarity information, and three-dimensional spatial information. After obtaining the vector representations from the model, we grouped and filtered 3,724 natural small molecules and 14 known mitophagy inducers from our database. In the end, we selected 18 small molecules for validation in ‘wet lab’ experiments. Our team then used human HeLa cells, and nematode and mouse models, to validate the autophagy-inducing capacity of these molecules. The final two candidate molecules are kaempferol and rhodopsin tannoy. Both induce significant autophagy in the nervous systems of human cells, nematodes, and mice. More importantly, we found that kaempferol and rhodopsin tannoy have a significant positive effect on neurodegenerative changes in mice with AD. These changes include inhibition of AD pathology (aggregation of amyloid and microtubule-associated proteins) and improvement in learning and memory. This provides compelling new evidence for the activation of mitophagy as an AD therapeutic strategy. Nature Biomedical Engineering, one of the world’s leading academic journals, has published our research results online (https://doi. org/10.1038/s41551-021-00819-5). UM professor Lu Jiahong is a co-author and UM PhD student Zhuang Xuxu is a co-first author. AI Empowers Drug Discovery Modern drug development is a costly process that involves initial screening for biological activities and identification of lead compounds. This is followed by 研究員在患有阿爾茨海默病的三重轉基因小鼠身上驗證兩款線粒體自噬激活劑的功效。這些免疫熒光染色圖顯示小鼠的大腦皮質和海馬體中對AT8抗體呈陽性的 細胞。放大的藍框和紅框內是指定的大腦區域。 The researchers validated the capabilities of the two mitophagy inducers in triple-transgenic mice with AD. These immunofluorescence staining images show AT8-positive cells in the cortex and hippocampus of these mice. The magnified blue and red boxes show the designated brain regions. 2021 UMAGAZINE 24
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