{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T01:27:36Z","timestamp":1773797256865,"version":"3.50.1"},"reference-count":32,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T00:00:00Z","timestamp":1567728000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005616","name":"Memorial University of Newfoundland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005616","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":[[2019,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>5\u2010fluorouracil (5\u2010FU) is an anticancer drug, which inhibits human thymidine phosphorylase (hTP) and plays a key role in maintaining the process of DNA replication and repair. It is involved in regulating pyrimidine nucleotide production, by which it inhibits the mechanism of cell proliferation and cancerous tumor growth. However, up to 80% of the administered drug is metabolized by dihydropyrimidine dehydrogenase (DPD). This work compares binding of 5\u2010FU and its analogues to hTP and DPD, and suggests strategies to reduce drug binding to DPD to decrease the required dose of 5\u2010FU. An important feature between the proteins studied here was the difference of charge distribution in their binding sites, which can be exploited for designing drugs to selectively bind to the hTP. The 5\u2010FU presence was thought to be required for a closed conformation. Comparison of the calculation results pertaining to unliganded and liganded protein showed that hTP could still undergo open\u2013closed conformations in the absence of the ligand; however, the presence of a positively charged ligand better stabilizes the closed conformation and rigidifies the core region of the protein more than unliganded or neutral liganded system. The study has also shown that one of the three hinge segments linking the two major \u03b1 and \u03b1\/\u03b2 domains of the hTP is an important contributing factor to the enzyme's open\u2013close conformational twist during its inactivation\u2013activation process. In addition, the angle between the \u03b1\/\u03b2\u2010domain and the \u03b1\u2010domain has shown to undergo wide rotations over the course of MD simulation in the absence of a phosphate, suggesting that it contributes to the stabilization of the closed conformation of the hTP.<\/jats:p>","DOI":"10.1111\/cbdd.13596","type":"journal-article","created":{"date-parts":[[2019,7,29]],"date-time":"2019-07-29T17:09:27Z","timestamp":1564420167000},"page":"1956-1972","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Interdomain twists of human thymidine phosphorylase and its active\u2013inactive conformations: Binding of 5\u2010FU and its analogues to human thymidine phosphorylase versus dihydropyrimidine dehydrogenase"],"prefix":"10.1111","volume":"94","author":[{"given":"Tiffany","family":"Tozer","sequence":"first","affiliation":[{"name":"School of Pharmacy Memorial University of Newfoundland St. John\u2019s Newfoundland Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kali","family":"Heale","sequence":"additional","affiliation":[{"name":"School of Pharmacy Memorial University of Newfoundland St. John\u2019s Newfoundland Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Manto Chagas","sequence":"additional","affiliation":[{"name":"School of Pharmacy Memorial University of Newfoundland St. John\u2019s Newfoundland Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andre Luis Branco","family":"de Barros","sequence":"additional","affiliation":[{"name":"Department of Clinical and Toxicological Analysis Universidade Federal de Minas Gerais (UFMG) Belo Horizonte Minas Gerais Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8874-5909","authenticated-orcid":false,"given":"Laleh","family":"Alisaraie","sequence":"additional","affiliation":[{"name":"School of Pharmacy Memorial University of Newfoundland St. John\u2019s Newfoundland Canada"},{"name":"Department of Chemistry Memorial University of Newfoundland St. John's Newfoundland Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,9,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr900095e"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007999920146"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2018.07.046"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct300323g"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.4.650"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20060513"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.7b00112"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1999.3371"},{"key":"e_1_2_8_11_1","first-page":"63","article-title":"Comparison of protein force fields for molecular","volume":"443","author":"Guvench O.","year":"2008","journal-title":"Dynamics Simulations"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.240470304"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct700301q"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.2"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00376a009"},{"issue":"11","key":"e_1_2_8_17_1","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1016\/S0021-9258(18)93352-1","article-title":"Pentosyl transfer mechanisms of the mammalian nucleoside phosphorylases","volume":"243","author":"Krenitsky T. 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