{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:10:04Z","timestamp":1785859804404,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","doi-asserted-by":"publisher","award":["24K18664"],"award-info":[{"award-number":["24K18664"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kurozumi Medical Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Acute myeloid leukemia (AML) remains a therapeutic challenge due to complex oncogenic networks, including the often-undruggable MYC pathway. Here, we present an integrated in silico framework combining transcriptomic analysis, machine learning, and molecular dynamics (MD) simulations to explore potential therapeutic approaches targeting vault RNA1-1 (VTRNA1-1) in AML. RNA-seq profiling revealed that VTRNA1-1 depletion is associated with a profound disruption of the MYC and FOXM1 regulatory axes. To highlight compounds capable of recapitulating this transcriptomic signature, we developed a machine learning pipeline utilizing a Random Forest classifier trained on a fully compiled L1000FWD database subset. Virtual screening of approved drugs predicted the anthelmintic niclosamide as a top candidate (98.17% mimic probability). Explainable AI further rationalized this prediction by highlighting specific fragments within niclosamide\u2019s salicylanilide core. Furthermore, a 200 ns MD simulation indicated favorable computational stability of niclosamide bound to the p62 (SQSTM1) ZZ domain. The complex showed rapid structural convergence (ligand RMSD plateauing at 1.65 nm) without dissociation, while maintaining strict receptor compactness (steady Radius of Gyration and solvent-accessible surface area) and a persistent interaction network of ~73 close atomic contacts. These findings suggest that niclosamide may function as a stable physical \u201clid\u201d over the p62 ZZ domain, occluding its N-degron-binding cleft. Taken together, our computational framework highlights niclosamide as a promising candidate for AML drug repurposing, providing a hypothesis-generating foundation that warrants rigorous experimental validation.<\/jats:p>","DOI":"10.3390\/biology15151290","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T15:08:09Z","timestamp":1785856089000},"page":"1290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Docking and Simulation-Based Exploration of Niclosamide as a Potential Inhibitor of the p62 ZZ Domain"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5256-1913","authenticated-orcid":false,"given":"Yuki","family":"Hatayama","sequence":"first","affiliation":[{"name":"Division of Clinical Laboratory, Tottori University Hospital, Tottori 683-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Shimohiro","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Science and Technology, School of Health Science, Faculty of Medicine, Tottori University, Tottori 683-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Division of Clinical Laboratory, Tottori University Hospital, Tottori 683-8504, Japan"},{"name":"Division of Clinical Laboratory Medicine, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori 683-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s11912-024-01503-y","article-title":"Novel Therapeutic Targets in Acute Myeloid Leukemia (AML)","volume":"26","author":"Wysota","year":"2024","journal-title":"Curr. Oncol. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.blre.2019.04.005","article-title":"Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges","volume":"36","author":"Shallis","year":"2019","journal-title":"Blood Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s13045-019-0774-x","article-title":"Recent drug approvals for acute myeloid leukemia","volume":"12","author":"Lai","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41408-021-00425-3","article-title":"Acute myeloid leukemia: Current progress and future directions","volume":"11","author":"Kantarjian","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e441","DOI":"10.1038\/bcj.2016.50","article-title":"Acute myeloid leukemia: A comprehensive review and 2016 update","volume":"6","year":"2016","journal-title":"Blood Cancer J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"zcaf028","DOI":"10.1093\/narcan\/zcaf028","article-title":"Regulation of angiogenesis and cancer cell proliferation by human vault RNA1-2","volume":"7","author":"Gallo","year":"2025","journal-title":"NAR Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gallo, S., Kong, E., Ferro, I., and Polacek, N. (2022). Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis. Cancers, 14.","DOI":"10.3390\/cancers14112787"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1080\/15548627.2021.1922983","article-title":"The human vault RNA enhances tumorigenesis and chemoresistance through the lysosome in hepatocellular carcinoma","volume":"18","author":"Ferro","year":"2022","journal-title":"Autophagy"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bracher, L., Ferro, I., Pulido-Quetglas, C., Ruepp, M.D., Johnson, R., and Polacek, N. (2020). Human vtRNA1-1 Levels Modulate Signaling Pathways and Regulate Apoptosis in Human Cancer Cells. Biomolecules, 10.","DOI":"10.3390\/biom10040614"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"182","DOI":"10.12688\/f1000research.28510.2","article-title":"Pan-cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology","volume":"10","author":"Fort","year":"2021","journal-title":"F1000Res"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7030","DOI":"10.1038\/ncomms8030","article-title":"Expression of the vault RNA protects cells from undergoing apoptosis","volume":"6","author":"Amort","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Taube, M., Lisiak, N., Toto\u0144, E., and Rubi\u015b, B. (2024). Human Vault RNAs: Exploring Their Potential Role in Cellular Metabolism. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25074072"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Maniatis, A., Rizopoulou, D., Shaukat, A.N., Grafanaki, K., Stamatopoulou, V., and Stathopoulos, C. (2025). Vault Particles in Cancer Progression, Multidrug Resistance, and Drug Delivery: Current Insights and Future Applications. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26041562"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.gendis.2023.01.014","article-title":"Vault RNAs (vtRNAs): Rediscovered non-coding RNAs with diverse physiological and pathological activities","volume":"11","year":"2024","journal-title":"Genes Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8971","DOI":"10.1074\/jbc.273.15.8971","article-title":"Vaults are up-regulated in multidrug-resistant cancer cell lines","volume":"273","author":"Kickhoefer","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13077","DOI":"10.3892\/mmr.2023.13077","article-title":"Serum levels of vault RNA significantly varied in patients with haematological malignancies","volume":"28","author":"Kato","year":"2023","journal-title":"Mol. Med. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102018","DOI":"10.1016\/j.mcp.2025.102018","article-title":"Serum vault RNA1-1 levels reflect blood cells and bone marrow","volume":"80","author":"Hatayama","year":"2025","journal-title":"Mol. Cell. Probes"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1093\/bioinformatics\/bty060","article-title":"L1000FWD: Fireworks visualization of drug-induced transcriptomic signatures","volume":"34","author":"Wang","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1080\/15548627.2019.1609861","article-title":"Vault RNA emerges as a regulator of selective autophagy","volume":"15","author":"Horos","year":"2019","journal-title":"Autophagy"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/j.cell.2019.01.030","article-title":"The Small Non-coding Vault RNA1-1 Acts as a Riboregulator of Autophagy","volume":"176","author":"Horos","year":"2019","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1261\/rna.079129.122","article-title":"Vault RNA1-1 riboregulates the autophagic function of p62 by binding to lysine 7 and arginine 21, both of which are critical for p62 oligomerization","volume":"28","author":"Horos","year":"2022","journal-title":"RNA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/s41422-019-0167-2","article-title":"RNA binding to p62 impacts selective autophagy","volume":"29","author":"Misra","year":"2019","journal-title":"Cell Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"R297","DOI":"10.1016\/j.cub.2019.03.008","article-title":"Selective Autophagy: RNA Comes from the Vault to Regulate p62\/SQSTM1","volume":"29","author":"Johansen","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100703","DOI":"10.1016\/j.drup.2020.100703","article-title":"Genetic biomarkers of drug resistance: A compass of prognosis and targeted therapy in acute myeloid leukemia","volume":"52","author":"Long","year":"2020","journal-title":"Drug Resist. Updates"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41419-024-06810-7","article-title":"Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia","volume":"15","author":"Nwosu","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ferrara, F., Lessi, F., Vitagliano, O., Birkenghi, E., and Rossi, G. (2019). Current Therapeutic Results and Treatment Options for Older Patients with Relapsed Acute Myeloid Leukemia. Cancers, 11.","DOI":"10.3390\/cancers11020224"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102154","DOI":"10.1016\/j.ctrv.2021.102154","article-title":"MYC as a target for cancer treatment","volume":"94","author":"Duffy","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gu, K., May, H.A., and Kang, M.H. (2024). Targeting Molecular Signaling Pathways and Cytokine Responses to Modulate c-MYC in Acute Myeloid Leukemia. Front. Biosci., 16.","DOI":"10.31083\/j.fbs1603015"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"117111","DOI":"10.1016\/j.bcp.2025.117111","article-title":"A novel 3-alkenylindol-2-one derivative selectively inhibits the growth of acute myeloid leukemia via modulation of the MYC-PRMT pathway","volume":"240","author":"Dong","year":"2025","journal-title":"Biochem. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13045-023-01424-6","article-title":"Recent advances in targeted therapies in acute myeloid leukemia","volume":"16","author":"Bhansali","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1038\/s41375-021-01224-2","article-title":"Downregulation of MTSS1 in acute myeloid leukemia is associated with a poor prognosis, chemotherapy resistance, and disease aggressiveness","volume":"35","author":"Grandits","year":"2021","journal-title":"Leukemia"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hamdoun, S., Jung, P., and Efferth, T. (2017). Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00110"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"117527","DOI":"10.1016\/j.ejmech.2025.117527","article-title":"Pharmacological advances and therapeutic applications of niclosamide in cancer and other diseases","volume":"290","author":"Laila","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jiang, H., Li, A.M., and Ye, J. (2022). The magic bullet: Niclosamide. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1004978"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1158\/0008-5472.CAN-09-3950","article-title":"Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: Inactivation of the NF-kappaB pathway and generation of reactive oxygen species","volume":"70","author":"Jin","year":"2010","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4301","DOI":"10.18632\/oncotarget.23794","article-title":"Niclosamide suppresses acute myeloid leukemia cell proliferation through inhibition of CREB-dependent signaling pathways","volume":"9","author":"Chae","year":"2018","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1038\/s41467-018-05825-x","article-title":"Insights into degradation mechanism of N-end rule substrates by p62\/SQSTM1 autophagy adapter","volume":"9","author":"Kwon","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41467-017-00085-7","article-title":"p62\/SQSTM1\/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis","volume":"8","author":"Yu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4373","DOI":"10.1038\/s41467-018-06878-8","article-title":"ZZ-dependent regulation of p62\/SQSTM1 in autophagy","volume":"9","author":"Zhang","year":"2018","journal-title":"Nat. Commun."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/15\/1290\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T15:15:10Z","timestamp":1785856510000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/15\/1290"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":39,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["biology15151290"],"URL":"https:\/\/doi.org\/10.3390\/biology15151290","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}