🤖 AI Summary
This study addresses the challenge of developing highly specific, synthetically accessible small-molecule degraders for intracellular toxic Aβ-42 protein in Alzheimer’s disease by proposing a molecular glue design strategy leveraging the ubiquitin–proteasome system. The authors innovatively integrate conditional information of E3 ligases (CRBN, VHL, and MDM2) into a generative model, constructing a Ligase-Conditioned Junction Tree Variational Autoencoder (LC-JT-VAE) that combines protein sequence embeddings with torsion-aware molecular graphs. The framework further incorporates structural docking and ADMET filtering to prioritize viable candidates. This approach successfully generates novel, chemically synthesizable, and ligase-selective molecular glues capable of mediating ternary complex formation between Aβ-42 and E3 ligases, demonstrating promising potential for promoting Aβ-42 degradation and offering a new therapeutic paradigm for neurodegenerative diseases.
📝 Abstract
Alzheimer’s disease (AD) is marked by the pathological accumulation of amyloid beta-42 (Aβ42), contributing to synaptic dysfunction and neurodegeneration. While extracellular amyloid plaques are well-studied, increasing evidence highlights intracellular Aβ42 as an early and toxic driver of disease progression. In this study, we present a novel, Generative AI–based drug design approach to promote targeted degradation of Aβ42 via the ubiquitin–proteasome system (UPS), using E3 ligase–directed molecular glues. We systematically evaluated the ternary complex formation potential of Aβ42 with three E3 ligases (CRBN, VHL, and MDM2) through structure-based modeling, ADMET screening, and docking. We then developed a Ligase-Conditioned Junction Tree Variational Autoencoder (LC-JT-VAE) to generate ligase-specific small molecules, incorporating protein sequence embeddings and torsional angle-aware molecular graphs. Our results demonstrate that this generative model can produce chemically valid, novel, and target-specific molecular glues capable of facilitating Aβ42 degradation. This integrated approach offers a promising framework for designing UPS-targeted therapies for neurodegenerative diseases.