{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T11:27:22Z","timestamp":1787052442218,"version":"3.56.0"},"reference-count":93,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T00:00:00Z","timestamp":1625702400000},"content-version":"vor","delay-in-days":682,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["18883"],"award-info":[{"award-number":["18883"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sklodowska-Curie Actions","doi-asserted-by":"publisher","award":["746309"],"award-info":[{"award-number":["746309"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM126363"],"award-info":[{"award-number":["GM126363"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Veterans Administration","award":["I01 Bx002198"],"award-info":[{"award-number":["I01 Bx002198"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human type II topoisomerases (TopoII) are essential for controlling DNA topology within the cell. For this reason, there are a number of TopoII-targeted anticancer drugs that act by inducing DNA cleavage mediated by both TopoII isoforms (TopoII\u03b1 and TopoII\u03b2) in cells. However, recent studies suggest that specific poisoning of TopoII\u03b1 may be a safer strategy for treating cancer. This is because poisoning of TopoII\u03b2 appears to be linked to the generation of secondary leukemia in patients. We recently reported that enzyme-mediated DNA cleavage complexes (in which TopoII is covalently linked to the cleaved DNA during catalysis) formed in the presence of the anticancer drug etoposide persisted approximately 3-fold longer with TopoII\u03b1 than TopoII\u03b2. Notably, enhanced drug-target residence time may reduce the adverse effects of specific TopoII\u03b1 poisons. However, it is still not clear how to design drugs that are specific for the \u03b1 isoform. In this study, we report the results of classical molecular dynamics (MD) simulations to comparatively analyze the molecular interactions formed within the TopoII\/DNA\/etoposide complex with both isoforms. We also used smoothed potential MD to estimate etoposide dissociation kinetics from the two isoform complexes. These extensive classical and enhanced sampling simulations revealed stabilizing interactions of etoposide with two serine residues (Ser763 and Ser800) in TopoII\u03b1. These interactions are missing in TopoII\u03b2, where both amino acids are alanine residues. This may explain the greater persistence of etoposide-stabilized cleavage complexes formed with Topo TopoII\u03b1. These findings could be useful for the rational design of specific TopoII\u03b1 poisons.<\/jats:p>","DOI":"10.1021\/acs.jcim.9b00605","type":"journal-article","created":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T15:22:48Z","timestamp":1566832968000},"page":"4007-4017","source":"Crossref","is-referenced-by-count":12,"title":["Smoothed Potential MD Simulations for Dissociation\nKinetics of Etoposide To Unravel Isoform Specificity in Targeting\nHuman Topoisomerase II"],"prefix":"10.1021","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0355-4773","authenticated-orcid":true,"given":"Jissy\nA.","family":"Kuriappan","sequence":"first","affiliation":[{"name":"Istituto Italiano di Tecnologia , , Via Morego 30 , ,","place":["Genova, Italy, 16163"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2550-4884","authenticated-orcid":true,"given":"Neil","family":"Osheroff","sequence":"additional","affiliation":[{"name":"Vanderbilt University School of Medicine , , , ,","place":["Nashville, Tennessee, United States, 37232-0146"]},{"name":"Vanderbilt University School of Medicine , , , ,","place":["Nashville, Tennessee, United States, 37232-6307"]},{"name":"VA Tennessee Valley Healthcare System , , ,","place":["Nashville, Tennessee, United States, 37212"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4022-5661","authenticated-orcid":true,"given":"Marco","family":"De Vivo","sequence":"additional","affiliation":[{"name":"Istituto Italiano di Tecnologia , , Via Morego 30 , ,","place":["Genova, Italy, 16163"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,8,26]]},"reference":[{"key":"2026081805123778800_cit1","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1021\/cb300648v","article-title":"Drugging Topoisomerases:\nLessons and Challenges","volume":"8","author":"Pommier","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"2026081805123778800_cit2","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1038\/s41467-018-03705-y","article-title":"Progress and\nChallenges Towards Targeted Delivery of Cancer Therapeutics","volume":"9","author":"Rosenblum","year":"2018","journal-title":"Nat. Commun."},{"key":"2026081805123778800_cit3","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/nrm.2016.111","article-title":"Roles of Eukaryotic Topoisomerases\nin Transcription, Replication and Genomic Stability","volume":"17","author":"Pommier","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026081805123778800_cit4","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nrc2608","article-title":"DNA Topoisomerase\nII and Its Growing Repertoire of Biological Functions","volume":"9","author":"Nitiss","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"2026081805123778800_cit5","doi-asserted-by":"publisher","first-page":"6595","DOI":"10.1021\/bi5010816","article-title":"Catalytic Core of Human Topoisomerase\nII\u03b1: Insights into Enzyme-DNA Interactions and Drug Mechanism","volume":"53","author":"Lindsey","year":"2014","journal-title":"Biochemistry"},{"key":"2026081805123778800_cit6","doi-asserted-by":"publisher","first-page":"4883","DOI":"10.1093\/nar\/gkn466","article-title":"Human Topoisomerase II\u03b1 Uses\na Two-Metal-Ion Mechanism for DNA Cleavage","volume":"36","author":"Deweese","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"2026081805123778800_cit7","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1039\/c003759a","article-title":"The Use of Divalent Metal Ions by Type II Topoisomerases","volume":"2","author":"Deweese","year":"2010","journal-title":"Metallomics"},{"key":"2026081805123778800_cit8","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1021\/ar500314j","article-title":"Catalytic Metal Ions and Enzymatic\nProcessing of DNA and Rna","volume":"48","author":"Palermo","year":"2015","journal-title":"Acc. Chem. Res."},{"key":"2026081805123778800_cit9","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.2741\/3809","article-title":"Bridging Quantum Mechanics and Structure-Based Drug Design","volume":"16","author":"De\nVivo","year":"2011","journal-title":"Front. Biosci., Landmark Ed."},{"key":"2026081805123778800_cit10","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1021\/ct300691u","article-title":"Molecular Simulations Highlight the\nRole of Metals\nin Catalysis and Inhibition of Type II Topoisomerase","volume":"9","author":"Palermo","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"2026081805123778800_cit11","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1146\/annurev.biochem.70.1.369","article-title":"DNA Topoisomerases:\nStructure, Function, and Mechanism","volume":"70","author":"Champoux","year":"2001","journal-title":"Annu. 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Cancer"},{"key":"2026081805123778800_cit15","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.mrfmmm.2012.07.005","article-title":"The DNA Topoisomerase II Catalytic\nInhibitor Merbarone Is Genotoxic and Induces Endoreduplication","volume":"738\u2013739","author":"Pastor","year":"2012","journal-title":"Mutat. Res., Fundam. Mol. Mech. Mutagen."},{"key":"2026081805123778800_cit16","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/B978-0-12-812522-9.00005-1","article-title":"Inhibitors\nand Poisons of Mammalian\nType II Topoisomerases","volume":"11","author":"Murphy","year":"2017","journal-title":"Adv. Mol. Toxic."},{"key":"2026081805123778800_cit17","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.chembiol.2010.04.012","article-title":"DNA Topoisomerases and Their Poisoning\nby Anticancer and Antibacterial Drugs","volume":"17","author":"Pommier","year":"2010","journal-title":"Chem.\nBiol."},{"key":"2026081805123778800_cit18","doi-asserted-by":"publisher","first-page":"3611","DOI":"10.1021\/cr200325f","article-title":"Contemporary\nChallenges in the Design of Topoisomerase II Inhibitors for Cancer\nChemotherapy","volume":"112","author":"Bailly","year":"2012","journal-title":"Chem. Rev."},{"key":"2026081805123778800_cit19","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1039\/C8MD00219C","article-title":"Identification of Potent\nCatalytic Inhibitors of Human DNA Topoisomerase\nII by Structure-Based Virtual Screening","volume":"9","author":"Dong","year":"2018","journal-title":"MedChemComm"},{"key":"2026081805123778800_cit20","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1016\/j.bmcl.2012.12.063","article-title":"Indenoindolone\nDerivatives\nas Topoisomerase II-Inhibiting Anticancer Agents","volume":"23","author":"Kashyap","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081805123778800_cit21","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1042\/BCJ20160583","article-title":"Topoisomerases\nas Anticancer\nTargets","volume":"475","author":"Delgado","year":"2018","journal-title":"Biochem. 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Biol. Chem."},{"key":"2026081805123778800_cit25","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/nrd3404","article-title":"Interfacial Inhibitors:\nTargeting Macromolecular Complexes","volume":"11","author":"Pommier","year":"2012","journal-title":"Nat. Rev.\nDrug Discovery"},{"key":"2026081805123778800_cit26","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1016\/j.bmcl.2016.02.034","article-title":"Inhibition of Human DNA Topoisomerase II\u03b1 by Two Novel Ellipticine\nDerivatives","volume":"26","author":"Vann","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081805123778800_cit27","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1021\/acs.chemrestox.6b00209","article-title":"Two-Mechanism Model\nfor the Interaction of Etoposide Quinone with Topoisomerase II\u03b1","volume":"29","author":"Gibson","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"2026081805123778800_cit28","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/S0921-4410(03)21005-X","article-title":"Topoisomerase\nII Inhibitors","volume":"21","author":"Hande","year":"2003","journal-title":"Cancer Chemother. Biol. Response\nModif."},{"key":"2026081805123778800_cit29","doi-asserted-by":"publisher","first-page":"2474","DOI":"10.2174\/1381612811319130016","article-title":"Recent Developments of DNA Poisons--Human\nDNA Topoisomerase II\u03b1 Inhibitors--as Anticancer Agents","volume":"19","author":"Pogorelcnik","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"2026081805123778800_cit30","doi-asserted-by":"publisher","first-page":"363","DOI":"10.2174\/1568011054222364","article-title":"Etoposide, Topoisomerase II and Cancer","volume":"5","author":"Baldwin","year":"2005","journal-title":"Curr. Med. Chem.: Anti-Cancer Agents"},{"key":"2026081805123778800_cit31","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1111\/joa.12416","article-title":"Distinct\nExpression Patterns for\nType II Topoisomerases II\u03b1 and II\u03b2 in the Early Foetal\nHuman Telencephalon","volume":"228","author":"Harkin","year":"2016","journal-title":"J. Anat."},{"key":"2026081805123778800_cit32","first-page":"209","article-title":"Proliferation-\nand Cell Cycle-Dependent Differences in Expression of the 170 Kilodalton\nand 180 Kilodalton Forms of Topoisomerase II in Nih-3t3 Cells","volume":"2","author":"Woessner","year":"1991","journal-title":"Cell Growth Differ."},{"key":"2026081805123778800_cit33","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1083\/jcb.200112023","article-title":"Dynamics of Human DNA Topoisomerases\nII\u03b1 and II\u03b2 in Living Cells","volume":"157","author":"Christensen","year":"2002","journal-title":"J.\nCell Biol."},{"key":"2026081805123778800_cit34","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1093\/nar\/gkn937","article-title":"The DNA Cleavage Reaction of Topoisomerase II: Wolf\nin Sheep\u2019s Clothing","volume":"37","author":"Deweese","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2026081805123778800_cit35","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1111\/nyas.12358","article-title":"Topoisomerase II and\nLeukemia","volume":"1310","author":"Pendleton","year":"2014","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2026081805123778800_cit36","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1002\/(SICI)1521-1878(199803)20:3&lt;215::AID-BIES5&gt;3.0.CO;2-Q","article-title":"Eukaryotic DNA Topoisomerase\nII Beta","volume":"20","author":"Austin","year":"1998","journal-title":"BioEssays"},{"key":"2026081805123778800_cit37","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1126\/science.287.5450.131","article-title":"DNA Topoisomerase\nIIbeta and Neural Development","volume":"287","author":"Yang","year":"2000","journal-title":"Science"},{"key":"2026081805123778800_cit38","doi-asserted-by":"publisher","first-page":"1798","DOI":"10.1126\/science.1127196","article-title":"A Topoisomerase\nII\u03b2-Mediated dsDNA Break Required for Regulated Transcription","volume":"312","author":"Ju","year":"2006","journal-title":"Science"},{"key":"2026081805123778800_cit39","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1007\/s12264-010-0625-9","article-title":"The Function of DNA Topoisomerase IIbeta in Neuronal Development","volume":"26","author":"Heng","year":"2010","journal-title":"Neurosci. Bull."},{"key":"2026081805123778800_cit40","doi-asserted-by":"publisher","first-page":"3229","DOI":"10.1021\/bi500421q","article-title":"Etoposide\nQuinone Is a Covalent Poison of Human Topoisomerase II\u03b2","volume":"53","author":"Smith","year":"2014","journal-title":"Biochemistry"},{"key":"2026081805123778800_cit41","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.mrfmmm.2007.06.009","article-title":"DNA Topoisomerase II, Genotoxicity, and Cancer","volume":"623","author":"McClendon","year":"2007","journal-title":"Mutat. Res., Fundam. Mol. Mech. Mutagen."},{"key":"2026081805123778800_cit42","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1124\/mol.54.1.78","article-title":"Etoposide\nTargets Topoisomerase II\u03b1 and II\u03b2 in Leukemic Cells: Isoform-Specific\nCleavable Complexes Visualized and Quantified in Situ by a Novel Immunofluorescence\nTechnique","volume":"54","author":"Willmore","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"2026081805123778800_cit43","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/s002800050978","article-title":"Carbamate Analogues\nof Amsacrine Active against Non-Cycling Cells: Relative Activity against\nTopoisomerases II\u03b1 and II\u03b2","volume":"44","author":"Turnbull","year":"1999","journal-title":"Cancer\nChemother. Pharmacol."},{"key":"2026081805123778800_cit44","doi-asserted-by":"publisher","first-page":"4049","DOI":"10.1021\/acsomega.8b03428","article-title":"Examining\nthe Impact of Antimicrobial Fluoroquinolones on Human DNA Topoisomerase\nII\u03b1 and II\u03b2","volume":"4","author":"Fief","year":"2019","journal-title":"ACS Omega"},{"key":"2026081805123778800_cit45","doi-asserted-by":"publisher","first-page":"2996","DOI":"10.1021\/acschembio.6b00565","article-title":"Phenanthriplatin\nActs as a Covalent Poison of Topoisomerase II Cleavage Complexes","volume":"11","author":"Riddell","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"2026081805123778800_cit46","doi-asserted-by":"publisher","first-page":"4019","DOI":"10.1038\/onc.2014.332","article-title":"Topoisomerase II\u03b1\nin Chromosome Instability and Personalized Cancer Therapy","volume":"34","author":"Chen","year":"2015","journal-title":"Oncogene"},{"key":"2026081805123778800_cit47","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1021\/acs.chemrestox.8b00204","article-title":"Structural and Metal Ion Effects\non Human Topoisomerase II\u03b1 Inhibition by Alpha-(N)-Heterocyclic\nThiosemicarbazones","volume":"32","author":"Morris","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"2026081805123778800_cit48","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1021\/acs.chemrestox.6b00009","article-title":"Effects of Secondary\nMetabolites from the Fungus Septofusidium\nBerolinense on DNA Cleavage Mediated by Human Topoisomerase II\u03b1","volume":"29","author":"Vann","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"2026081805123778800_cit49","doi-asserted-by":"publisher","first-page":"8989","DOI":"10.1073\/pnas.1204406109","article-title":"Model for Mll Translocations in Therapy-Related\nLeukemia Involving Topoisomerase IIbeta-Mediated DNA Strand Breaks\nand Gene Proximity","volume":"109","author":"Cowell","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.\nS. A."},{"key":"2026081805123778800_cit50","doi-asserted-by":"publisher","first-page":"11014","DOI":"10.1073\/pnas.0704002104","article-title":"Roles of DNA Topoisomerase II Isozymes\nin Chemotherapy and Secondary Malignancies","volume":"104","author":"Azarova","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081805123778800_cit51","doi-asserted-by":"publisher","first-page":"2075","DOI":"10.3390\/ijerph9062075","article-title":"Mechanism of Generation\nof Therapy Related Leukemia\nin Response to Anti-Topoisomerase II Agents","volume":"9","author":"Cowell","year":"2012","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"2026081805123778800_cit52","doi-asserted-by":"publisher","first-page":"5013","DOI":"10.1021\/jm200235u","article-title":"N-Fused Imidazoles\nas Novel Anticancer\nAgents That Inhibit Catalytic Activity of Topoisomerase II\u03b1\nand Induce Apoptosis in G1\/S Phase","volume":"54","author":"Baviskar","year":"2011","journal-title":"J. Med.\nChem."},{"key":"2026081805123778800_cit53","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1021\/acsmedchemlett.5b00040","article-title":"Switch in Site of\nInhibition: A Strategy for Structure-Based\nDiscovery of Human Topoisomerase II\u03b1 Catalytic Inhibitors","volume":"6","author":"Baviskar","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"2026081805123778800_cit54","doi-asserted-by":"publisher","first-page":"4687","DOI":"10.1016\/j.bmcl.2017.09.011","article-title":"Novel Xanthone-Polyamine\nConjugates as Catalytic Inhibitors of Human Topoisomerase II\u03b1","volume":"27","author":"Minniti","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026081805123778800_cit55","doi-asserted-by":"publisher","first-page":"11009","DOI":"10.1038\/srep11009","article-title":"Egcg Regulates\nthe\nCross-Talk between Jwa and Topoisomerase II\u03b1 in Non-Small-Cell\nLung Cancer (Nsclc) Cells","volume":"5","author":"Li","year":"2015","journal-title":"Sci. Rep."},{"key":"2026081805123778800_cit56","doi-asserted-by":"publisher","first-page":"4851","DOI":"10.1021\/acs.jmedchem.5b00473","article-title":"Differential\nTargeting of Human Topoisomerase II Isoforms\nwith Small Molecules","volume":"58","author":"Mariani","year":"2015","journal-title":"J. Med. 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