{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T12:13:15Z","timestamp":1792411995306,"version":"4.4.0"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,1,20]],"date-time":"2020-01-20T00:00:00Z","timestamp":1579478400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000001","name":"Alberta Cancer Foundation","doi-asserted-by":"publisher","award":["26603"],"award-info":[{"award-number":["26603"]}],"id":[{"id":"10.13039\/501100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009192","name":"Alberta Innovates","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009192","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009009","name":"Novartis Pharmaceuticals Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000190","name":"University of Alberta","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The heterodimer of DNA excision repair protein ERCC\u20101 and DNA repair endonuclease XPF (ERCC1\u2010XPF) is a 5\u2032\u20133\u2032 structure\u2010specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1\u2010XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum\u2010based and cross\u2010linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1\u2010XPF interaction (<jats:italic>Molecular Pharmacology<\/jats:italic>, <jats:bold>84<\/jats:bold>, 2013 and 12), to improve its binding to the target. We followed a multi\u2010step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, <jats:bold>B5<\/jats:bold>, showed an improved half\u2010maximum inhibitory concentration (IC<jats:sub>50<\/jats:sub>) value of 0.49\u00a0\u00b5M for the inhibition of ERCC1\u2010XPF endonuclease activit, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1\u2010XPF complex.<\/jats:p>","DOI":"10.1111\/cbdd.13660","type":"journal-article","created":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T11:23:27Z","timestamp":1577791407000},"page":"460-471","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Computer\u2010aided drug design of small molecule inhibitors of the ERCC1\u2010XPF protein\u2013protein interaction"],"prefix":"10.1111","volume":"95","author":[{"given":"Francesco","family":"Gentile","sequence":"first","affiliation":[{"name":"Department of Physics University of Alberta Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed H.","family":"Elmenoufy","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Alberta Edmonton AB Canada"},{"name":"Department of Pharmaceutical Chemistry College of Pharmacy Misr University for Science and Technology 6th of October City Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Ciniero","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering Politecnico di Torino Torino Italy"},{"name":"Universit\u00e0 di Torino Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Jay","sequence":"additional","affiliation":[{"name":"Department of Oncology Cross Cancer Institute University of Alberta Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feridoun","family":"Karimi\u2010Busheri","sequence":"additional","affiliation":[{"name":"Department of Oncology Cross Cancer Institute University of Alberta Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled H.","family":"Barakat","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Weinfeld","sequence":"additional","affiliation":[{"name":"Department of Oncology Cross Cancer Institute University of Alberta Edmonton AB Canada"},{"name":"Cancer Research Institute of Northern Alberta University of Alberta Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick G.","family":"West","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Alberta Edmonton AB Canada"},{"name":"Cancer Research Institute of Northern Alberta University of Alberta Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9976-0429","authenticated-orcid":false,"given":"Jack A.","family":"Tuszynski","sequence":"additional","affiliation":[{"name":"Department of Physics University of Alberta Edmonton AB Canada"},{"name":"Department of Mechanical and Aerospace Engineering Politecnico di Torino Torino Italy"},{"name":"Department of Oncology Cross Cancer Institute University of Alberta Edmonton AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,20]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks375"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12072"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2010.03.010"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051329"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks284"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0860"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2017.12.035"},{"key":"e_1_2_8_9_1","volume-title":"Amber 15","author":"Case D.","year":"2015"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2015.08.031"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2015.08.024"},{"key":"e_1_2_8_12_1","volume-title":"Molecular Operating Environment (MOE), 2015","author":"Chemical Computing Group Inc","year":"2015"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2663"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.18.4146"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00326"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23123205"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1517\/17460441.2015.1032936"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19051328"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612822666160420141435"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmgm.2016.02.010"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2052520616003954"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2342"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.10128"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.112.082347"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.445869"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/bip.360221211"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmgm.2015.09.010"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20933"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct400146w"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct500918t"},{"key":"e_1_2_8_32_1","volume-title":"Overview of pharmacophore applications in MOE","author":"Lin A.","year":"2004"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.039"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00255"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2015.04.002"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks818"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.303"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct300418h"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S139336"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.20033"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct400314y"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-417205-0.00014-6"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/24.17.3370"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5b00559"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2005.08.014"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20035"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20035"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(19990130)20:2<217::AID-JCC4>3.0.CO;2-A"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci990307l"}],"container-title":["Chemical Biology &amp; Drug Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcbdd.13660","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.13660","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cbdd.13660","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.13660","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T22:44:23Z","timestamp":1694040263000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cbdd.13660"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,20]]},"references-count":48,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1111\/cbdd.13660"],"URL":"https:\/\/doi.org\/10.1111\/cbdd.13660","archive":["Portico"],"relation":{},"ISSN":["1747-0277","1747-0285"],"issn-type":[{"value":"1747-0277","type":"print"},{"value":"1747-0285","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,20]]},"assertion":[{"value":"2019-09-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}