{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T15:34:32Z","timestamp":1766504072332,"version":"build-2065373602"},"reference-count":51,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"This research was supported by MEXT\/JSPS KAKENHI awarded to A.K.","award":["Nos. JP23H02445, JP23H04058, JP23H02424, JP24H02259, and JP24H01357"],"award-info":[{"award-number":["Nos. JP23H02445, JP23H04058, JP23H02424, JP24H02259, and JP24H01357"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Comput Aided Mol Des"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>DockIT is a tool for interactive molecular docking that can model both the local and global conformational response of the receptor to the docking of a ligand based on information from a molecular dynamics simulation. Using DockIT we have investigated the binding process of two histone deacetylase (HDAC) inhibitors to HDAC6: the nonselective approved drug belinostat and the preclinical HPOB. To model HDAC6\u2019s conformational response to the binding of the inhibitors we performed a 200-nanosecond explicit-solvent molecular dynamics simulation on HDAC6. Unexpectedly the simulation revealed a domain movement that affects the size and shape of the binding pocket. Using automated docking and a rigid model for the inhibitors, the domain movement continuously adapts the pocket to the presence of the inhibitor. For both inhibitors, an intermediate binding site was found where it was partially inserted, with a hydrogen bond formed between the inhibitor\u2019s hydroxamic acid and the Tyr745 side chain. Pushing the inhibitor deeper into the pocket over an energy barrier and re-engaging automated docking, a final binding pose resulted with a root-mean square deviation with its respective crystallographic pose of 1.0 \u00c5 for belinostat and 1.4 \u00c5 for HPOB. We believe our results mimic substrate recognition by the enzyme, with an initial partial binding of the acetyllysine residue with Tyr745. During binding a relay of hydrogen bonds occurs coordinating the orientation of the cap and the hydroxamic acid inside the pocket. The interaction between the cap and the surface of HDAC6 explains the reason for the hydroxamic acid warhead in HPOB binding in a flipped orientation compared to belinostat.<\/jats:p>","DOI":"10.1007\/s10822-025-00636-x","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T15:27:24Z","timestamp":1752593244000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protein domain movement involved in binding of belinostat and HPOB as inhibitors of histone deacetylase 6 (HDAC6): a hybrid automated-interactive docking study"],"prefix":"10.1007","volume":"39","author":[{"given":"Georgios","family":"Iakovou","sequence":"first","affiliation":[]},{"given":"L.","family":"Palmer","sequence":"additional","affiliation":[]},{"given":"A.","family":"Ganesan","sequence":"additional","affiliation":[]},{"given":"Akio","family":"Kitao","sequence":"additional","affiliation":[]},{"given":"Stephen D.","family":"Laycock","sequence":"additional","affiliation":[]},{"given":"Steven","family":"Hayward","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"issue":"8","key":"636_CR1","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1021\/acs.accounts.3c00801","volume":"57","author":"DW Christianson","year":"2024","unstructured":"Christianson DW (2024) Acc Chem Res 57(8):1135","journal-title":"Acc Chem Res"},{"key":"636_CR2","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.sbi.2019.01.004","volume":"59","author":"NJ Porter","year":"2019","unstructured":"Porter NJ, Christianson DW (2019) Curr Opin Struct Biol 59:9","journal-title":"Curr Opin Struct Biol"},{"issue":"21","key":"636_CR3","doi-asserted-by":"publisher","first-page":"12460","DOI":"10.1021\/acs.jmedchem.0c00830","volume":"63","author":"TCS Ho","year":"2020","unstructured":"Ho TCS, Chan AHY, Ganesan A (2020) J Med Chem 63(21):12460","journal-title":"J Med Chem"},{"key":"636_CR4","doi-asserted-by":"publisher","first-page":"117185","DOI":"10.1016\/j.ejmech.2024.117185","volume":"283","author":"Z Lv","year":"2025","unstructured":"Lv Z, Ji T, Liu J, Sun X, Liang H (2025) Eur J Med Chem 283:117185","journal-title":"Eur J Med Chem"},{"issue":"9","key":"636_CR5","doi-asserted-by":"publisher","first-page":"104094","DOI":"10.1016\/j.drudis.2024.104094","volume":"29","author":"YS Raouf","year":"2024","unstructured":"Raouf YS (2024) Drug Discovery Today 29(9):104094","journal-title":"Drug Discovery Today"},{"key":"636_CR6","doi-asserted-by":"publisher","first-page":"117218","DOI":"10.1016\/j.biopha.2024.117218","volume":"178","author":"Z Huang","year":"2024","unstructured":"Huang Z, Li L, Cheng B, Li D (2024) Biomed Pharmacother 178:117218","journal-title":"Biomed Pharmacother"},{"issue":"3","key":"636_CR7","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1021\/acs.jmedchem.0c01782","volume":"64","author":"X-H Zhang","year":"2021","unstructured":"Zhang X-H, Qin M, Wu H-P, Khamis MY, Li Y-H, Ma L-Y, Liu H-M (2021) J Med Chem 64(3):1362","journal-title":"J Med Chem"},{"key":"636_CR8","doi-asserted-by":"crossref","unstructured":"Lee J-H, Mahendran A, Yao Y, Ngo L, Venta-Perez G, Choy ML, Kim N, Ham W-S, Breslow R, Marks PA (2013) Proceedings of the National Academy of Sciences 110(39):15704","DOI":"10.1073\/pnas.1313893110"},{"issue":"13","key":"636_CR9","doi-asserted-by":"publisher","first-page":"3307","DOI":"10.1158\/1078-0432.CCR-16-2526","volume":"23","author":"DT Vogl","year":"2017","unstructured":"Vogl DT, Raje N, Jagannath S, Richardson P, Hari P, Orlowski R, Supko JG, Tamang D, Yang M, Jones SS, Wheeler C, Markelewicz RJ, Lonial S (2017) Clin Cancer Res 23(13):3307","journal-title":"Clin Cancer Res"},{"issue":"9","key":"636_CR10","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1038\/nchembio.2134","volume":"12","author":"Y Hai","year":"2016","unstructured":"Hai Y, Christianson DW (2016) Nat Chem Biol 12(9):741","journal-title":"Nat Chem Biol"},{"key":"636_CR11","doi-asserted-by":"crossref","unstructured":"Li XD, Liu XA, Wang SS, Shi XX, Lu M, Hao XY, Fu Y, Zhang Y, Jia QZ, He D (2022) Bioorganic Chemistry 125","DOI":"10.1016\/j.bioorg.2022.105874"},{"issue":"48","key":"636_CR12","doi-asserted-by":"publisher","first-page":"21201","DOI":"10.1039\/D0NJ04704J","volume":"44","author":"H Chu","year":"2020","unstructured":"Chu H, He QX, Wang J, Hu Y, Wang YQ, Lin ZH (2020) New J Chem 44(48):21201","journal-title":"New J Chem"},{"issue":"22","key":"636_CR13","doi-asserted-by":"publisher","first-page":"18786","DOI":"10.1021\/acsomega.2c01572","volume":"7","author":"A Mishra","year":"2022","unstructured":"Mishra A, Singh A (2022) Acs Omega 7(22):18786","journal-title":"Acs Omega"},{"key":"636_CR14","doi-asserted-by":"crossref","unstructured":"AbdElmoniem N, Abdallah MH, Mukhtar RM, Moutasim F, Ahmed AR, Edris A, Ibraheem W, Makki AA, Elshamly EM, Elhag R, Osman W, Mothana RA, Alzain AA (2023) Molecules 28(4)","DOI":"10.3390\/molecules28041771"},{"issue":"3","key":"636_CR15","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1021\/acschemneuro.8b00405","volume":"10","author":"A Zeb","year":"2019","unstructured":"Zeb A, Park C, Rampogu S, Son M, Lee G, Lee KW (2019) ACS Chem Neurosci 10(3):1326","journal-title":"ACS Chem Neurosci"},{"key":"636_CR16","doi-asserted-by":"publisher","first-page":"122395","DOI":"10.1016\/j.lfs.2023.122395","volume":"338","author":"AI Uba","year":"2024","unstructured":"Uba AI, Hryb M, Singh M, Bui-Linh C, Tran A, Atienza J, Misbah S, Mou X, Wu C (2024) Life Sci 338:122395","journal-title":"Life Sci"},{"issue":"1","key":"636_CR17","doi-asserted-by":"publisher","first-page":"14466","DOI":"10.1038\/s41598-023-41325-9","volume":"13","author":"M Shahab","year":"2023","unstructured":"Shahab M, Al-Madhagi H, Zheng G, Zeb A, Alasmari AF, Alharbi M, Alasmari F, Khan MQ, Khan M, Wadood A (2023) Sci Rep 13(1):14466","journal-title":"Sci Rep"},{"issue":"9","key":"636_CR18","doi-asserted-by":"publisher","first-page":"4225","DOI":"10.1021\/ct400361k","volume":"9","author":"A Magno","year":"2013","unstructured":"Magno A, Steiner S, Caflisch A (2013) J Chem Theory Comput 9(9):4225","journal-title":"J Chem Theory Comput"},{"key":"636_CR19","doi-asserted-by":"crossref","unstructured":"Baaden M, Glowacki DR (2025) Current Opinion in Structural Biology 92:103044","DOI":"10.1016\/j.sbi.2025.103044"},{"issue":"24","key":"636_CR20","doi-asserted-by":"publisher","first-page":"5698","DOI":"10.1093\/bioinformatics\/btaa1059","volume":"36","author":"G Iakovou","year":"2020","unstructured":"Iakovou G, Alhazzazi M, Hayward S, Laycock S (2020) Bioinformatics 36(24):5698","journal-title":"Bioinformatics"},{"issue":"2","key":"636_CR21","doi-asserted-by":"publisher","first-page":"19","DOI":"10.20870\/IJVR.2009.8.2.2720","volume":"8","author":"S Cakici","year":"2009","unstructured":"Cakici S, Sumengen S, Sezerman U, Balcisoy S (2009) Int J Virtual Real 8(2):19","journal-title":"Int J Virtual Real"},{"key":"636_CR22","doi-asserted-by":"crossref","unstructured":"O\u2019Connor MB, Bennie SJ, Deeks HM, Jamieson-Binnie A, Jones AJ, Shannon RJ, Walters R, Mitchell TJ, Mulholland AJ, Glowacki DR (2019) J Chem Phys 150(22)","DOI":"10.1063\/1.5092590"},{"key":"636_CR23","doi-asserted-by":"crossref","unstructured":"Plateau-Holleville C, Guionni\u00e8re S, Boyer B, Jim\u00e9nez-Garcia B, Levieux G, M\u00e9rillou S, Maria M, Montes M (2023) Bioinformatics 39(10)","DOI":"10.1093\/bioinformatics\/btad609"},{"issue":"6","key":"636_CR24","doi-asserted-by":"publisher","first-page":"2514","DOI":"10.1021\/acs.jchemed.4c01347","volume":"102","author":"G Iakovou","year":"2025","unstructured":"Iakovou G, Palmer L, Ganesan A, Kitao A, Laycock SD, Hayward S (2025) J Chem Educ 102(6):2514","journal-title":"J Chem Educ"},{"key":"636_CR25","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1039\/C3FD00123G","volume":"169","author":"G Iakovou","year":"2014","unstructured":"Iakovou G, Hayward S, Laycock S (2014) Faraday Discuss 169:359","journal-title":"Faraday Discuss"},{"key":"636_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jmgm.2015.06.003","volume":"61","author":"G Iakovou","year":"2015","unstructured":"Iakovou G, Hayward S, Laycock SD (2015) J Mol Graph Model 61:1","journal-title":"J Mol Graph Model"},{"issue":"5","key":"636_CR27","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1021\/acs.jcim.7b00051","volume":"57","author":"G Iakovou","year":"2017","unstructured":"Iakovou G, Hayward S, Laycock SD (2017) J Chem Inf Model 57(5):1142","journal-title":"J Chem Inf Model"},{"issue":"6","key":"636_CR28","doi-asserted-by":"publisher","first-page":"2900","DOI":"10.1021\/acs.jcim.9b00112","volume":"59","author":"N Matthews","year":"2019","unstructured":"Matthews N, Kitao A, Laycock S, Hayward S (2019) J Chem Inf Model 59(6):2900","journal-title":"J Chem Inf Model"},{"issue":"23","key":"636_CR29","doi-asserted-by":"publisher","first-page":"5855","DOI":"10.1021\/acs.jcim.2c01274","volume":"62","author":"G Iakovou","year":"2022","unstructured":"Iakovou G, Laycock SD, Hayward S (2022) J Chem Inf Model 62(23):5855","journal-title":"J Chem Inf Model"},{"issue":"11","key":"636_CR30","doi-asserted-by":"publisher","first-page":"1810","DOI":"10.1021\/acsmedchemlett.1c00425","volume":"12","author":"G Sandrone","year":"2021","unstructured":"Sandrone G, Cukier CD, Zrubek K, Marchini M, Vergani B, Caprini G, Fossati G, Steinkuhler C, Stevenazzi A (2021) ACS Med Chem Lett 12(11):1810","journal-title":"ACS Med Chem Lett"},{"key":"636_CR31","doi-asserted-by":"crossref","unstructured":"He X, Man VH, Yang W, Lee T-S, Wang J (2020) J Chem Phys 153(11)","DOI":"10.1063\/5.0019056"},{"issue":"20","key":"636_CR32","doi-asserted-by":"publisher","first-page":"6183","DOI":"10.1021\/acs.jcim.3c01153","volume":"63","author":"DA Case","year":"2023","unstructured":"Case DA, Aktulga HM, Belfon K, Cerutti DS, Cisneros GA, Cruzeiro VWD, Forouzesh N, Giese TJ, G\u00f6tz AW, Gohlke H, Izadi S, Kasavajhala K, Kaymak MC, King E, Kurtzman T, Lee T-S, Li P, Liu J, Luchko T, Luo R, Manathunga M, Machado MR, Nguyen HM, O\u2019Hearn KA, Onufriev AV, Pan F, Pantano S, Qi R, Rahnamoun A, Risheh A, Schott-Verdugo S, Shajan A, Swails J, Wang J, Wei H, Wu X, Wu Y, Zhang S, Zhao S, Zhu Q, Cheatham TE, Roe III, Roitberg DR, Simmerling A, York C, Nagan DM, Merz MC Jr (2023) J Chem Inf Model 63(20):6183","journal-title":"J Chem Inf Model"},{"issue":"7","key":"636_CR33","doi-asserted-by":"publisher","first-page":"3077","DOI":"10.1021\/acs.jctc.7b00102","volume":"13","author":"T-S Lee","year":"2017","unstructured":"Lee T-S, Hu Y, Sherborne B, Guo Z, York DM (2017) J Chem Theory Comput 13(7):3077","journal-title":"J Chem Theory Comput"},{"issue":"19","key":"636_CR34","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1002\/jcc.25187","volume":"39","author":"DJ Mermelstein","year":"2018","unstructured":"Mermelstein DJ, Lin C, Nelson G, Kretsch R, McCammon JA, Walker RC (2018) J Comput Chem 39(19):1354","journal-title":"J Comput Chem"},{"issue":"10","key":"636_CR35","doi-asserted-by":"publisher","first-page":"2043","DOI":"10.1021\/acs.jcim.8b00462","volume":"58","author":"T-S Lee","year":"2018","unstructured":"Lee T-S, Cerutti DS, Mermelstein D, Lin C, LeGrand S, Giese TJ, Roitberg A, Case DA, Walker RC, York DM (2018) J Chem Inf Model 58(10):2043","journal-title":"J Chem Inf Model"},{"issue":"21","key":"636_CR36","doi-asserted-by":"publisher","first-page":"3863","DOI":"10.1021\/jz501780a","volume":"5","author":"S Izadi","year":"2014","unstructured":"Izadi S, Anandakrishnan R, Onufriev AV (2014) J Phys Chem Lett 5(21):3863","journal-title":"J Phys Chem Lett"},{"issue":"1","key":"636_CR37","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1021\/acs.jctc.9b00591","volume":"16","author":"C Tian","year":"2020","unstructured":"Tian C, Kasavajhala K, Belfon KAA, Raguette L, Huang H, Migues AN, Bickel J, Wang Y, Pincay J, Wu Q, Simmerling C (2020) J Chem Theory Comput 16(1):528","journal-title":"J Chem Theory Comput"},{"issue":"7","key":"636_CR38","doi-asserted-by":"publisher","first-page":"2064","DOI":"10.1021\/acs.jctc.2c01255","volume":"19","author":"M Smith","year":"2023","unstructured":"Smith M, Li Z, Landry L, Merz KM Jr., Li P (2023) J Chem Theory Comput 19(7):2064","journal-title":"J Chem Theory Comput"},{"issue":"3","key":"636_CR39","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s10930-023-10113-9","volume":"42","author":"S Hayward","year":"2023","unstructured":"Hayward S (2023) Protein J 42(3):181","journal-title":"Protein J"},{"issue":"2","key":"636_CR40","first-page":"298","volume":"5","author":"A Kitao","year":"2022","unstructured":"Kitao A (2022) J 5(2):298","journal-title":"J"},{"key":"636_CR41","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1002\/(SICI)1097-0134(19980201)30:2<144::AID-PROT4>3.0.CO;2-N","volume":"30","author":"S Hayward","year":"1998","unstructured":"Hayward S, Berendsen HJC (1998) Proteins 30:144","journal-title":"Proteins"},{"issue":"10","key":"636_CR42","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1093\/bioinformatics\/btg137","volume":"19","author":"RA Lee","year":"2003","unstructured":"Lee RA, Razaz M, Hayward S (2003) Bioinformatics 19(10):1290","journal-title":"Bioinformatics"},{"key":"636_CR43","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1002\/(SICI)1097-0134(19990901)36:4<425::AID-PROT6>3.0.CO;2-S","volume":"36","author":"S Hayward","year":"1999","unstructured":"Hayward S (1999) Proteins 36:425","journal-title":"Proteins"},{"issue":"22","key":"636_CR44","doi-asserted-by":"publisher","first-page":"3189","DOI":"10.1093\/bioinformatics\/btu506","volume":"30","author":"D Taylor","year":"2014","unstructured":"Taylor D, Cawley G, Hayward S (2014) Bioinformatics 30(22):3189","journal-title":"Bioinformatics"},{"key":"636_CR45","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-1-0716-3985-6_1","volume-title":"Protein-Protein docking: methods and protocols","author":"KJ Kuder","year":"2024","unstructured":"Kuder KJ (2024) Docking foundations: from rigid to flexible Docking. In: Kaczor AA (ed) Protein-Protein docking: methods and protocols. Springer US, New York, NY, p 3"},{"issue":"2","key":"636_CR46","doi-asserted-by":"publisher","first-page":"146","DOI":"10.2174\/157340911795677602","volume":"7","author":"XY Meng","year":"2011","unstructured":"Meng XY, Zhang HX, Mezei M, Cui M (2011) Curr Comput Aided Drug Des 7(2):146","journal-title":"Curr Comput Aided Drug Des"},{"issue":"2","key":"636_CR47","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.sbi.2010.02.001","volume":"20","author":"M Zacharias","year":"2010","unstructured":"Zacharias M (2010) Curr Opin Struct Biol 20(2):180","journal-title":"Curr Opin Struct Biol"},{"key":"636_CR48","doi-asserted-by":"crossref","unstructured":"May A, Zacharias M (2008) Proteins: Structure, Function, and Bioinformatics 70(3):794","DOI":"10.1002\/prot.21579"},{"issue":"8","key":"636_CR49","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1093\/protein\/4.8.903","volume":"4","author":"EL Mehler","year":"1991","unstructured":"Mehler EL, Solmajer T (1991) Protein Eng 4(8):903","journal-title":"Protein Eng"},{"key":"636_CR50","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1529\/biophysj.106.085910","volume":"91","author":"S Hayward","year":"2006","unstructured":"Hayward S, Kitao A (2006) Biophys J 91:1823","journal-title":"Biophys J"},{"issue":"2","key":"636_CR51","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/s12276-020-0382-4","volume":"52","author":"SY Park","year":"2020","unstructured":"Park SY, Kim JS (2020) Exp Mol Med 52(2):204","journal-title":"Exp Mol Med"}],"container-title":["Journal of Computer-Aided Molecular Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-025-00636-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10822-025-00636-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10822-025-00636-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T18:02:23Z","timestamp":1762452143000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10822-025-00636-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,15]]},"references-count":51,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["636"],"URL":"https:\/\/doi.org\/10.1007\/s10822-025-00636-x","relation":{},"ISSN":["0920-654X","1573-4951"],"issn-type":[{"type":"print","value":"0920-654X"},{"type":"electronic","value":"1573-4951"}],"subject":[],"published":{"date-parts":[[2025,7,15]]},"assertion":[{"value":"28 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"52"}}