{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T17:21:30Z","timestamp":1772212890627,"version":"3.50.1"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Object<\/jats:title>\n                    <jats:p>To identify novel targets for the diagnosis, treatment and prognosis of cholangiocarcinoma, we screen ideal lead compounds and preclinical drug candidates with MYC inhibitory effect from the ZINC database, and verify the therapeutic effect of Dhea and 2\u201314,15-Eg on cholangiocarcinoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The gene expression profiles of GSE132305, GSE89749, and GSE45001 were obtained respectively from the Gene Expression Omnibus database. The DEGs were identified by comparing the gene expression profiles of cholangiocarcinoma and normal tissues. GO, KEGG analysis and PPI network analyses were performed. LibDock, ADME and toxicity prediction, molecular docking and molecular dynamics simulations were used to identify potential inhibitors of MYC. Moreover, in vitro, MTT assay, colony-forming assay, the scratch assay and Western blotting were performed to verify the therapeutic effect of Dhea and 2\u201314,15-Eg.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PPI network analysis showed that ALB, MYC, APOB, IGF1 and KNG1 were hub genes, of which MYC was mainly studied in this study. A battery of computer-aided virtual techniques showed that Dhea and 2\u201314,15-Eg have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6, as well as could exist stably in natural circumstances. In vitro assays showed that Dhea and 2\u201314,15-Eg inhibited cholangiocarcinoma cellular viability, proliferation, and migration inhibiting expression of MYC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study suggested that Dhea and 2\u201314,15-Eg were novel potential inhibitors of MYC targeting, as well as are a promising drug in dealing with cholangiocarcinoma and have a perspective application.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0260180","type":"journal-article","created":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T13:53:44Z","timestamp":1643896424000},"page":"e0260180","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Selected by bioinformatics and molecular docking analysis, Dhea and 2\u201314,15-Eg are effective 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Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise.","volume":"21","author":"SK Saha","year":"2016","journal-title":"Oncologist"},{"issue":"1","key":"pone.0260180.ref002","doi-asserted-by":"crossref","first-page":"e1800128","DOI":"10.1002\/prca.201800128","article-title":"Proteomic Landscape of Cholangiocarcinomas Reveals Three Different Subgroups According to Their Localization and the Aspect of Non-Tumor Liver.","volume":"13","author":"J Le Faouder","year":"2019","journal-title":"Proteomics Clin Appl"},{"issue":"12","key":"pone.0260180.ref003","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1016\/j.dld.2020.08.030","article-title":"Italian Clinical Practice Guidelines on Cholangiocarcinoma\u2014Part II: Treatment.","volume":"52","author":"Cholangiocarcinoma Working Group","year":"2020","journal-title":"Dig Liver Dis"},{"issue":"Suppl 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Liu","year":"2019","journal-title":"PeerJ"},{"issue":"18","key":"pone.0260180.ref007","doi-asserted-by":"crossref","first-page":"4331","DOI":"10.3390\/ijms20184331","article-title":"Molecular Docking: Shifting Paradigms in Drug Discovery.","volume":"20","author":"L Pinzi","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"20","key":"pone.0260180.ref008","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.2174\/1568026617666170224121313","article-title":"Structure-based Virtual Screening Approaches in Kinase-directed Drug Discovery","volume":"17","author":"D Bajusz","year":"2017","journal-title":"Curr Top Med Chem"},{"issue":"2","key":"pone.0260180.ref009","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/157340911795677602","article-title":"Molecular docking: a powerful approach for structure-based drug discovery.","volume":"7","author":"XY Meng","year":"2011","journal-title":"Curr Comput Aided Drug Des"},{"issue":"18","key":"pone.0260180.ref010","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.2174\/1568026617666170130110827","article-title":"A Practical Guide to Molecular Docking and Homology Modelling for Medicinal Chemists","volume":"17","author":"AE Lohning","year":"2017","journal-title":"Curr Top Med Chem"},{"issue":"2","key":"pone.0260180.ref011","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/nrclinonc.2017.157","article-title":"Cholangiocarcinoma\u2014evolving concepts and therapeutic strategies.","volume":"15","author":"S Rizvi","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"pone.0260180.ref012","doi-asserted-by":"crossref","first-page":"9738","DOI":"10.18632\/aging.102422","article-title":"Selected by gene co-expression network and molecular docking analyses, ENMD-2076 is highly effective in glioblastoma-bearing rats","volume":"11","author":"S. Zhong","year":"2019","journal-title":"Aging (Albany NY)"},{"key":"pone.0260180.ref013","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1186\/s12935-021-02041-4","article-title":"Ten-gene signature reveals the significance of clinical prognosis and immuno-correlation of osteosarcoma and study on novel skeleton inhibitors regarding MMP9","volume":"21","author":"W. Li","year":"2021","journal-title":"Cancer Cell Int"},{"key":"pone.0260180.ref014","doi-asserted-by":"crossref","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"GEO: archive for functional genomics data sets\u2014update","volume":"41","author":"T. Barrett","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"pone.0260180.ref015","doi-asserted-by":"crossref","first-page":"556984","DOI":"10.3389\/fphar.2020.556984","article-title":"In Silico Prediction of Molecular Targets of Astragaloside IV for Alleviation of COVID-19 Hyperinflammation by Systems Network Pharmacology and Bioinformatic Gene Expression Analysis","volume":"11","author":"C. Ge","year":"2020","journal-title":"Front Pharmacol"},{"key":"pone.0260180.ref016","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Y. Zhou","year":"2019","journal-title":"Nat Commun"},{"key":"pone.0260180.ref017","doi-asserted-by":"crossref","first-page":"D447","DOI":"10.1093\/nar\/gku1003","article-title":"STRING v10: protein-protein interaction networks, integrated over the tree of life","volume":"43","author":"D Szklarczyk","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"pone.0260180.ref018","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"P. Shannon","year":"2003","journal-title":"Genome Res"},{"key":"pone.0260180.ref019","article-title":"An automated method for finding molecular complexes in large protein interaction networks","volume":"42","author":"G.D. Bader","year":"2003","journal-title":"BMC Bioinformatics"},{"key":"pone.0260180.ref020","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1021\/acsomega.9b02263","article-title":", et al, Discovery of Lonafarnib-Like Compounds: Pharmacophore Modeling and Molecular Dynamics Studies.","volume":"5","author":"S. Rampogu","year":"2020","journal-title":"ACS Omega"},{"issue":"6","key":"pone.0260180.ref021","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1021\/ci6004299","article-title":"Validation studies of the site-directed docking program LibDock.","volume":"47","author":"SN Rao","year":"2007","journal-title":"J Chem Inf ModelNov-Dec"},{"issue":"10","key":"pone.0260180.ref022","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM: the biomolecular simulation program","volume":"30","author":"BR Brooks","year":"2009","journal-title":"J Comput Chem"},{"issue":"1","key":"pone.0260180.ref023","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s41065-020-00155-9","article-title":"Weighted gene co-expression network analysis revealed key biomarkers associated with the diagnosis of hypertrophic cardiomyopathy","volume":"157","author":"X Li","year":"2020","journal-title":"Hereditas"},{"key":"pone.0260180.ref024","author":"Q Jiang","year":"2020","journal-title":"J Cell Mol Med"},{"issue":"3","key":"pone.0260180.ref025","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1200\/JCO.2017.75.5009","article-title":"Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma.","volume":"36","author":"M Javle","year":"2018","journal-title":"J Clin Oncol"},{"key":"pone.0260180.ref026","first-page":"5976127","article-title":"Novel miRNA Predicts Survival and Prognosis of Cholangiocarcinoma Based on RNA-seq Data and In Vitro Experiments","volume":"2020","author":"Y Yao","year":"2020","journal-title":"Biomed Res Int"},{"issue":"1","key":"pone.0260180.ref027","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s12943-019-0991-5","article-title":"Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance","volume":"18","author":"L Mashouri","year":"2019","journal-title":"Mol Cancer"},{"issue":"5","key":"pone.0260180.ref028","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1093\/abbs\/gmaa028","article-title":"Exosomal piRNA profiling revealed unique circulating piRNA signatures of cholangiocarcinoma and gallbladder carcinoma","volume":"52","author":"X Gu","year":"2020","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"issue":"5","key":"pone.0260180.ref029","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1016\/j.celrep.2019.07.001","article-title":"Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas.","volume":"28","author":"LA Donehower","year":"2019","journal-title":"Cell Rep"},{"issue":"3","key":"pone.0260180.ref030","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/s41574-018-0126-x","article-title":"The obese adipose tissue microenvironment in cancer development and progression","volume":"15","author":"DF Quail","year":"2019","journal-title":"Nat Rev Endocrinol"},{"issue":"12","key":"pone.0260180.ref031","doi-asserted-by":"crossref","first-page":"e114398","DOI":"10.1371\/journal.pone.0114398","article-title":"MYC protein expression in primary diffuse large B-cell lymphoma of the central nervous system.","volume":"9","author":"KZ Gill","year":"2014","journal-title":"PLoS One"},{"issue":"2","key":"pone.0260180.ref032","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1158\/1055-9965.EPI-17-0637","article-title":"MYC Overexpression at the Protein and mRNA Level and Cancer Outcomes among Men Treated with Radical Prostatectomy for Prostate Cancer","volume":"27","author":"A Pettersson","year":"2018","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"1","key":"pone.0260180.ref033","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s12885-020-6604-2","article-title":"Nutritional assessment and prognosis of oral cancer patients: a large-scale prospective study","volume":"20","author":"X Bao","year":"2020","journal-title":"BMC Cancer"},{"issue":"6","key":"pone.0260180.ref034","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1177\/0194599818755995","article-title":"Which Assessment Method of Malnutrition in Head and Neck Cancer?","volume":"158","author":"N Saroul","year":"2018","journal-title":"Otolaryngol Head Neck Surg"},{"issue":"1","key":"pone.0260180.ref035","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1186\/s12885-017-3220-x","article-title":"The prognostic value of the preoperative c-reactive protein\/albumin ratio in ovarian cancer","volume":"17","author":"Y Liu","year":"2017","journal-title":"BMC Cancer"},{"issue":"4","key":"pone.0260180.ref036","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1159\/000487479","article-title":"The Prognostic Prediction Role of Preoperative Serum Albumin Level in Patients with Intahepatic Cholangiocarcinoma Following Hepatectomy.","volume":"36","author":"J Shen","year":"2018","journal-title":"Dig Dis"},{"issue":"11","key":"pone.0260180.ref037","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1002\/ijc.30013","article-title":"Apolipoproteins, lipids and risk of cancer","volume":"138","author":"S Borgquist","year":"2016","journal-title":"Int J Cancer"},{"issue":"12","key":"pone.0260180.ref038","first-page":"1407","article-title":"IGF1 polymorphisms and colon cancer risk","volume":"97","author":"H Dhifallah","year":"2019","journal-title":"Tunisian population. Tunis Med"},{"issue":"9","key":"pone.0260180.ref039","first-page":"1435","article-title":"Insulin\/IGF-1 signaling and aging","volume":"74","author":"T Sasako","year":"2016","journal-title":"Nihon Rinsho."},{"issue":"3","key":"pone.0260180.ref040","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.amjms.2015.12.013","article-title":"Insulin-Like Growth Factor-1 and Vascular Endothelial Growth Factor in Malignant and Benign Biliary Obstructions","volume":"351","author":"A Abdel-Razik","year":"2016","journal-title":"Am J Med Sci"},{"issue":"7","key":"pone.0260180.ref041","doi-asserted-by":"crossref","first-page":"e70519","DOI":"10.1371\/journal.pone.0070519","article-title":"Identification of kininogen-1 as a serum biomarker for the early detection of advanced colorectal adenoma and colorectal cancer","volume":"8","author":"J Wang","year":"2013","journal-title":"PLoS One"},{"issue":"1","key":"pone.0260180.ref042","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s13046-018-0833-0","article-title":"Overexpression of the Kininogen-1 inhibits proliferation and induces apoptosis of glioma cells","volume":"37","author":"J Xu","year":"2018","journal-title":"J Exp Clin Cancer Res"},{"issue":"5","key":"pone.0260180.ref043","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s40259-019-00370-5","article-title":"Mission Possible: Advances in MYC Therapeutic Targeting in Cancer.","volume":"33","author":"BL Allen-Petersen","year":"2019","journal-title":"BioDrugs"},{"issue":"5","key":"pone.0260180.ref044","doi-asserted-by":"crossref","first-page":"142","DOI":"10.3390\/genes8050142","article-title":"MYC-Master Regulator of the Cancer Epigenome and Transcriptome.","volume":"8","author":"CJ Poole","year":"2017","journal-title":"Genes (Basel)"},{"issue":"8","key":"pone.0260180.ref045","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1093\/annonc\/mdx157","article-title":"BET inhibitors: a novel epigenetic approach.","volume":"28","author":"DB Doroshow","year":"2017","journal-title":"Ann Oncol."},{"key":"pone.0260180.ref046","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ddtec.2017.10.003","article-title":"Novel approaches to targeting BRD4.","volume":"24","author":"OA Kharenko","year":"2017","journal-title":"Drug Discov Today Technol."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260180","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T13:54:17Z","timestamp":1643896457000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260180"}},"subtitle":[],"editor":[{"given":"Nafees","family":"Ahemad","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,3]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0260180","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-727120\/v1","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,3]]}}}