DeepDrugDiscovery identifies blood-brain barrier permeable autophagy enhancers for Alzheimer's disease

  • Nat Biomed Eng. 2026 Apr 24. doi: 10.1038/s41551-026-01667-x.
Yu Dong  #  1 ,  Xianglu Xiao  #  2  3  4 ,  Xu-Xu Zhuang  #  1 ,  Wenfan Wu  #  3  5  6 ,  Zi-Ying Wang  1  7 ,  Shuang Zhang  1  8 ,  Jin-Tao Li  1 ,  Ke Zhang  1 ,  Wen-Yu Fu  1 ,  Jun-Ming Chen  1 ,  Shi Hang Xiong  1 ,  Shenglong Deng  2  4 ,  Krinos Li  2 ,  Chao Ma  3 ,  Wangzhen Jin  3 ,  Xurui Jin  3 ,  Qiwei Cai  3 ,  Han-Ming Shen  9 ,  Min Li  10 ,  Huanxing Su  1 ,  Jian-Bo Wan  1 ,  Hua Yu  1 ,  Defang Ouyang  1  11 ,  Keqiang Ye  12 ,  Evandro F Fang  13  14 ,  Chris Soon Heng Tan  8 ,  Guang Yang  2  15  16  17 ,  Zhangming Niu  18  19  20 ,  Jia-Hong Lu  21
Affiliations
  • 1. State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China.
  • 2. Bioengineering Department and Imperial-X, Imperial College London, London, UK.
  • 3. Mindrank AI Ltd, Hangzhou, China.
  • 4. AI Research Center, MindRank Technologies Limited, London, UK.
  • 5. Department of Bioinformatics and Systems Biology, Huazhong University of Science and Technology, College of Life Sciences and Technology, Wuhan, China.
  • 6. Guangzhou National Laboratory, Guangzhou, China.
  • 7. Interdisciplinary Institute for Personalized Medicine in Brain Disorders, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.
  • 8. Department of Chemistry, School of Science, Southern University of Science and Technology, Shenzhen, China.
  • 9. Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China.
  • 10. Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
  • 11. Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macau SAR, China.
  • 12. Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology (SUAT), Shenzhen, China.
  • 13. Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.
  • 14. The Norwegian Centre on Healthy Ageing (NO-Age) and the Norwegian National anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway.
  • 15. National Heart and Lung Institute, Imperial College London, London, UK.
  • 16. Cardiovascular Research Centre, Royal Brompton Hospital, London, UK.
  • 17. School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK.
  • 18. Mindrank AI Ltd, Hangzhou, China. [email protected].
  • 19. AI Research Center, MindRank Technologies Limited, London, UK. [email protected].
  • 20. National Heart and Lung Institute, Imperial College London, London, UK. [email protected].
  • 21. State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China. [email protected].
  • # Contributed equally.
PMID: 42032039 DOI: 10.1038/s41551-026-01667-x
Abstract

Dysfunctional Autophagy, a key cellular cleaning process, is a key driver of brain ageing and neurodegenerative diseases such as Alzheimer's disease (AD). However, developing effective treatments by enhancing Autophagy has been challenging, as most known compounds act through the broad mTOR pathway, risking side effects, and few can effectively penetrate the brain. To address this, we developed DeepDrugDiscovery-a mechanism-aware, AI-powered screening platform incorporating ADMET and blood-brain barrier penetrability predictions. Here we show that this platform successfully identified novel, mTOR-independent Autophagy enhancers, with two lead compounds demonstrating an ability to cross the blood-brain barrier, clear AD-related protein aggregates and restore memory function in worm and mouse AD models. By releasing DeepDrugDiscovery as an open-source, modular tool, we offer a user-friendly AI platform that enables customized therapeutic screening. Our work establishes a scalable, AI-driven pipeline that integrates cross-species validation to rapidly discover mechanism-based therapeutics for diseases with high unmet medical need.

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