AI-Powered Platform DeepDrugDiscovery Identifies BBB-Permeable Autophagy Enhancers as Promising Candidates for Alzheimer’s Disease Therapy

May 01, 2026 12:00 CST Updated 12:00

MindRank

AI Drug Developer

iNature

Dysfunctional autophagy – a crucial cellular cleansing process – is a key driver of brain aging and neurodegenerative diseases such as Alzheimer's disease (AD).However, developing effective treatments by enhancing autophagy has been challenging because most known compounds act through the broad mTOR pathway, posing risks of side effects, and few compounds can effectively penetrate the brain.

April 24, 2026, Rui Lu from the University of Macau,MindRank Ltd.MindRank Ltd.InNature Biomedical Engineering（IF=26.7）InOnline PublicationTopicFor“DeepDrugDiscovery identifies blood–brain barrier permeable autophagy enhancers for Alzheimer’s disease”ResearchThesis.The StudyAn AI-driven drug screening platform named DeepDrugDiscovery has been developed. Through mechanism-aware virtual screening, it successfully identified two potent mTOR-independent autophagy enhancers that efficiently penetrate the blood-brain barrier—Omb (Maritimetin) and 2-HCA (2-Hydroxycinnamic Acid)—from a library of millions of molecules.

These two compounds can effectively clear Aβ and Tau aggregates and restore memory function in cellular, nematode, and mouse AD models, providing highly promising candidate drugs for AD treatment.

Autophagy is an evolutionarily conserved cellular process in eukaryotic cells that is crucial for the clearance of cellular waste and material recycling. This lysosome-dependent pathway degrades damaged and unnecessary cellular subunits (such as organelles and misfolded proteins), maintaining homeostasis in the central nervous system (CNS).An increasing body of evidence highlights the potential driving role of autophagy dysfunction in the pathogenesis and progression of neurodegenerative diseases, particularly Alzheimer's disease (AD).

The clinical translation of autophagy enhancers in AD remains challenging. Although most known autophagy enhancers act through mTOR-dependent pathways, their clinical translation is limited. Targeting mTOR-independent pathways is a promising alternative that may offer better safety. However, advancing this strategy is hindered by two major factors:The diversity of biological mechanisms targeted by drugs, and the inherent difficulty for such compounds to achieve sufficient blood-brain barrier (BBB) penetration.

DeepDrugDiscovery Workflow (Figure SourceNature Biomedical Engineering）

The study developed DeepDrugDiscovery – a mechanism-aware, AI-driven screening platform that integrates ADMET (absorption, distribution, metabolism, excretion, and toxicity) and blood-brain barrier (BBB) permeability prediction. The platform successfully identified novel mTOR-independent autophagy enhancers, with two lead compounds demonstrating the ability to cross the blood-brain barrier, clear AD-related protein aggregates, and restore memory function in worm and mouse AD models.This work establishes a scalable, AI-driven process integrating cross-species validation to rapidly discover mechanism-based treatments for diseases with high unmet medical needs.

Reference News:

https://www.nature.com/articles/s41551-026-01667-x

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