Conditioned Generative Modeling of Molecular Glues: A Realistic AI Approach for Synthesizable Drug-like Molecules.

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 li

SUBMITTER: Islam NN 

PROVIDER: S-EPMC12190558 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature