{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T21:58:21Z","timestamp":1790027901591,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Center for Individualized Medicine (CIM)","award":["24A19"],"award-info":[{"award-number":["24A19"]}]},{"name":"Florida Department of Health\u2014Ed and Ethel Moore Alzheimer\u2019s Disease Research Program","award":["24A19"],"award-info":[{"award-number":["24A19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is marked by the pathological accumulation of amyloid beta-42 (A\u03b242), contributing to synaptic dysfunction and neurodegeneration. While extracellular amyloid plaques are well-studied, increasing evidence highlights intracellular A\u03b242 as an early and toxic driver of disease progression. In this study, we present a novel, Generative AI\u2013based drug design approach to promote targeted degradation of A\u03b242 via the ubiquitin\u2013proteasome system (UPS), using E3 ligase\u2013directed molecular glues. We systematically evaluated the ternary complex formation potential of A\u03b242 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 A\u03b242 degradation. This integrated approach offers a promising framework for designing UPS-targeted therapies for neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/biom15060849","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T09:59:14Z","timestamp":1749549554000},"page":"849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Conditioned Generative Modeling of Molecular Glues: A Realistic AI Approach for Synthesizable Drug-like Molecules"],"prefix":"10.3390","volume":"15","author":[{"given":"Naeyma N.","family":"Islam","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1055-3069","authenticated-orcid":false,"given":"Thomas R.","family":"Caulfield","sequence":"additional","affiliation":[{"name":"Digital Ether Computing, Miami, FL33130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. 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