{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:01:59Z","timestamp":1792684919997,"version":"4.5.0"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Syst. Biol."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD), a neurodegenerative disorder, is characterized by its ability to cause memory loss and damage other cognitive functions. Aggregation of amyloid beta (A\u03b2) plaques and neurofibrillary tangles in the brain are responsible for the development of Alzheimer\u2019s disease (AD). While attempts targeting A\u03b2 and tau proteins have been extensively conducted in the past decades, only two FDA-approved drugs (i.e., monoclonal antibodies) tackle the underlying biology of Alzheimer\u2019s disease. In this study, an integrated computational framework was developed to identify new drug targets for Alzheimer\u2019s disease and identify small molecules as potential therapeutical options. A systematic investigation of the gene networks firstly revealed that the Apolipoprotein E4 (ApoE4) gene plays a central role among genes associated with Alzheimer\u2019s disease. The ApoE4 protein was then chosen as the protein target based on its role in the main pathological hallmarks of AD, which has been shown to increase A\u03b2 accumulation by directly binding to A\u03b2 as well as interfering with A\u03b2 clearance that is associated with other receptors. A library of roughly 1.5 million compounds was then virtually screened via a ligand-protein docking program to identify small-molecule compounds with potential binding capacity to the ApoE4 N-terminal domain. On the basis of compound properties, 312 compounds were selected, analyzed and clustered to further identify common structures and essential functional groups that play an important role in binding ApoE4. The <jats:italic>in silico<\/jats:italic> prediction suggested that compounds with four common structures of sulfon-amine-benzene, 1,2-benzisothiazol-3-amine 1,1-dioxide, N-phenylbenzamide, and furan-amino-benzene presented strong hydrogen bonds with residues E27, W34, R38, D53, D153, or Q156 in the N terminal of ApoE4. These structures might also form strong hydrophobic interactions with residues W26, E27, L28, L30, G31, L149, and A152. While the 312 compounds can serve as drug candidates for further experiment assays, the four common structures, along with the residues for hydrogen bond or hydrophobic interaction, pave the foundation to further optimize the compounds as better binders of ApoE4.<\/jats:p>","DOI":"10.3389\/fsysb.2023.1188430","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T05:41:03Z","timestamp":1686721263000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["A computational framework for identifying chemical compounds to bind Apolipoprotein E4 for Alzheimer\u2019s disease intervention"],"prefix":"10.3389","volume":"3","author":[{"given":"Tianhua","family":"Zhai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Krass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuyi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci8020027","article-title":"ABCA7 and pathogenic pathways of Alzheimer\u2019s disease","volume":"8","author":"Aikawa","year":"2018","journal-title":"Brain Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1002\/alz.12638","article-title":"Alzheimer\u2019s disease facts and figures","volume":"18","author":"Alzheimer's Association","year":"2022","journal-title":"Alzheimer\u2019s Dementia"},{"key":"B3","volume-title":"What is Alzheimer\u2019s disease? 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