{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T09:46:39Z","timestamp":1775209599317,"version":"3.50.1"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T00:00:00Z","timestamp":1480291200000},"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"],"DOI":"10.1371\/journal.pone.0167078","type":"journal-article","created":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T20:06:04Z","timestamp":1480363564000},"page":"e0167078","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Open Form Inducer Approach for Structure-Based Drug Design"],"prefix":"10.1371","volume":"11","author":[{"given":"Daniel Ken","family":"Inaoka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maiko","family":"Iida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Tabuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teruki","family":"Honma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nayoung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeru","family":"Matsuoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takefumi","family":"Kuranaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhito","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoo","family":"Shiba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimitoshi","family":"Sakamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel Oluwadare","family":"Balogun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeo","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Nara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josmar Rodrigues da","family":"Rocha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos Alberto","family":"Montanari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiko","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyoshi","family":"Kita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeharu","family":"Harada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2016,11,28]]},"reference":[{"issue":"3","key":"ref1","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1006\/clim.1999.4777","article-title":"Mechanism of action for leflunomide in rheumatoid arthritis","volume":"93","author":"RI Fox","year":"1999","journal-title":"Clin Immunol"},{"issue":"11","key":"ref2","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1136\/ard.59.11.841","article-title":"Leflunomide: mode of action in the treatment of rheumatoid arthritis","volume":"59","author":"FC Breedveld","year":"2000","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"ref3","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/BF00262414","article-title":"m-AMSA and PALA: two new agents in cancer chemotherapy","volume":"3","author":"M Rozencweig","year":"1979","journal-title":"Cancer Chemother Pharmacol"},{"issue":"1","key":"ref4","doi-asserted-by":"crossref","first-page":"31","DOI":"10.2174\/138945007779315524","article-title":"Targeting purine and pyrimidine metabolism in human apicomplexan parasites","volume":"8","author":"JE Hyde","year":"2007","journal-title":"Curr Drug Targets"},{"issue":"43","key":"ref5","doi-asserted-by":"crossref","first-page":"33373","DOI":"10.1074\/jbc.M004451200","article-title":"Helicobacter pylori-selective antibacterials based on inhibition of pyrimidine biosynthesis","volume":"275","author":"RA Copeland","year":"2000","journal-title":"J Biol Chem"},{"issue":"1","key":"ref6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0304-4165(82)90002-2","article-title":"UMP synthesis in the kinetoplastida","volume":"718","author":"DJ Hammond","year":"1982","journal-title":"Biochim Biophys Acta"},{"issue":"5733","key":"ref7","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.1112631","article-title":"The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease","volume":"309","author":"NM El-Sayed","year":"2005","journal-title":"Science"},{"issue":"1","key":"ref8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1365-2958.2008.06131.x","article-title":"Characterization of Trypanosoma brucei dihydroorotate dehydrogenase as a possible drug target; structural, kinetic and RNAi studies","volume":"68","author":"TL Arakaki","year":"2008","journal-title":"Mol Microbiol"},{"issue":"2","key":"ref9","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/mmi.12376","article-title":"Trypanosoma brucei (UMP synthase null mutants) are avirulent in mice, but recover virulence upon prolonged culture in vitro while retaining pyrimidine auxotrophy","volume":"90","author":"HB Ong","year":"2013","journal-title":"Mol Microbiol"},{"issue":"3","key":"ref10","doi-asserted-by":"crossref","first-page":"e58034","DOI":"10.1371\/journal.pone.0058034","article-title":"Pyrimidine biosynthesis is not an essential function for Trypanosoma brucei bloodstream forms","volume":"8","author":"JA Ali","year":"2013","journal-title":"PLoS One"},{"issue":"16","key":"ref11","doi-asserted-by":"crossref","first-page":"12759","DOI":"10.1074\/jbc.M112.346502","article-title":"Genetic dissection of pyrimidine biosynthesis and salvage in Leishmania donovani","volume":"287","author":"ZN Wilson","year":"2012","journal-title":"J Biol Chem"},{"issue":"1","key":"ref12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s00239-004-0078-8","article-title":"The origin of dihydroorotate dehydrogenase genes of kinetoplastids, with special reference to their biological significance and adaptation to anaerobic, parasitic conditions","volume":"60","author":"T Annoura","year":"2005","journal-title":"J Mol Evol"},{"issue":"3","key":"ref13","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.bbrc.2011.12.073","article-title":"Critical importance of the de novo pyrimidine biosynthesis pathway for Trypanosoma cruzi growth in the mammalian host cell cytoplasm","volume":"417","author":"M Hashimoto","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"issue":"1","key":"ref14","first-page":"20","article-title":"Evolutionary and functional families of dihydroorotate dehydrogenases","volume":"6","author":"O. Jensen KFaB","year":"1998","journal-title":"Paths to Pyrimidines"},{"issue":"2","key":"ref15","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0166-6851(02)00100-7","article-title":"Characterization of the dihydroorotate dehydrogenase as a soluble fumarate reductase in Trypanosoma cruzi","volume":"122","author":"E Takashima","year":"2002","journal-title":"Mol Biochem Parasitol"},{"issue":"41","key":"ref16","doi-asserted-by":"crossref","first-page":"10881","DOI":"10.1021\/bi800413r","article-title":"Structures of Trypanosoma cruzi dihydroorotate dehydrogenase complexed with substrates and products: atomic resolution insights into mechanisms of dihydroorotate oxidation and fumarate reduction","volume":"47","author":"DK Inaoka","year":"2008","journal-title":"Biochemistry"},{"issue":"12","key":"ref17","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/S0969-2126(00)00530-X","article-title":"Structure of dihydroorotate dehydrogenase B: electron transfer between two flavin groups bridged by an iron-sulphur cluster","volume":"8","author":"P Rowland","year":"2000","journal-title":"Structure"},{"issue":"1","key":"ref18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0969-2126(00)00077-0","article-title":"Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents","volume":"8","author":"S Liu","year":"2000","journal-title":"Structure"},{"issue":"2\u20133","key":"ref19","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/S0925-4439(02)00086-8","article-title":"Trypanosome alternative oxidase as a target of chemotherapy","volume":"1587","author":"C Nihei","year":"2002","journal-title":"Biochim Biophys Acta"},{"issue":"2","key":"ref20","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0166-6851(96)02797-1","article-title":"An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei","volume":"84","author":"N Minagawa","year":"1997","journal-title":"Mol Biochem Parasitol"},{"issue":"2","key":"ref21","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S1383-5769(03)00012-6","article-title":"The efficacy of ascofuranone in a consecutive treatment on Trypanosoma brucei brucei in mice","volume":"52","author":"Y Yabu","year":"2003","journal-title":"Parasitol Int"},{"issue":"1","key":"ref22","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.parint.2005.09.003","article-title":"Chemotherapeutic efficacy of ascofuranone in Trypanosoma vivax-infected mice without glycerol","volume":"55","author":"Y Yabu","year":"2006","journal-title":"Parasitol Int"},{"issue":"11","key":"ref23","doi-asserted-by":"crossref","first-page":"3163","DOI":"10.1158\/1078-0432.CCR-11-3090","article-title":"Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer","volume":"18","author":"CM Rudin","year":"2012","journal-title":"Clin Cancer Res"},{"issue":"1","key":"ref24","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1073\/pnas.98.1.60","article-title":"An anthelmintic compound, nafuredin, shows selective inhibition of complex I in helminth mitochondria","volume":"98","author":"S Omura","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ref25","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1128\/AAC.00378-07","article-title":"Anaerobic NADH-fumarate reductase system is predominant in the respiratory chain of Echinococcus multilocularis, providing a novel target for the chemotherapy of alveolar echinococcosis","volume":"52","author":"J Matsumoto","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"ref26","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1073\/pnas.0237315100","article-title":"Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase)","volume":"100","author":"H Miyadera","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"ref27","doi-asserted-by":"crossref","first-page":"4580","DOI":"10.1073\/pnas.1218386110","article-title":"Structure of the trypanosome cyanide-insensitive alternative oxidase","volume":"110","author":"T Shiba","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"Pt 9","key":"ref28","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1107\/S1744309109031352","article-title":"Crystallization of mitochondrial rhodoquinol-fumarate reductase from the parasitic nematode Ascaris suum with the specific inhibitor flutolanil","volume":"65","author":"A Osanai","year":"2009","journal-title":"Acta Crystallogr Sect F Struct Biol Cryst Commun"},{"issue":"6","key":"ref29","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/jb\/mvs051","article-title":"Crystal structure of mitochondrial quinol-fumarate reductase from the parasitic nematode Ascaris suum","volume":"151","author":"H Shimizu","year":"2012","journal-title":"J Biochem"},{"issue":"5","key":"ref30","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.bbabio.2013.01.005","article-title":"Diversity of parasite complex II","volume":"1827","author":"S Harada","year":"2013","journal-title":"Biochim Biophys Acta"},{"issue":"7","key":"ref31","doi-asserted-by":"crossref","first-page":"15287","DOI":"10.3390\/ijms160715287","article-title":"Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria","volume":"16","author":"D Inaoka","year":"2015","journal-title":"International Journal of Molecular Sciences"},{"issue":"4","key":"ref32","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1002\/cmdc.200900454","article-title":"Inhibition of human DHODH by 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids identified by structure-guided fragment selection","volume":"5","author":"I Fritzson","year":"2010","journal-title":"ChemMedChem"},{"issue":"9","key":"ref33","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1021\/jm800963t","article-title":"Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases","volume":"52","author":"M Davies","year":"2009","journal-title":"J Med Chem"},{"issue":"4","key":"ref34","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1021\/jm0506975","article-title":"Dual binding mode of a novel series of DHODH inhibitors","volume":"49","author":"R Baumgartner","year":"2006","journal-title":"J Med Chem"},{"issue":"15","key":"ref35","doi-asserted-by":"crossref","first-page":"5540","DOI":"10.1021\/jm200592f","article-title":"Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential","volume":"54","author":"JM Coteron","year":"2011","journal-title":"J Med Chem"},{"issue":"7","key":"ref36","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1021\/jm801343r","article-title":"Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice","volume":"52","author":"R Gujjar","year":"2009","journal-title":"J Med Chem"},{"issue":"3","key":"ref37","doi-asserted-by":"crossref","first-page":"226","DOI":"10.2174\/187152610791163336","article-title":"Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy","volume":"10","author":"MA Phillips","year":"2010","journal-title":"Infect Disord Drug Targets"},{"issue":"2","key":"ref38","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1021\/jm060687j","article-title":"Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase","volume":"50","author":"T Heikkila","year":"2007","journal-title":"J Med Chem"},{"issue":"7","key":"ref39","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/nrd1129","article-title":"Implications of protein flexibility for drug discovery","volume":"2","author":"SJ Teague","year":"2003","journal-title":"Nat Rev Drug Discov"},{"issue":"SUPPL","key":"ref40","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/S0026-0495(64)80018-4","article-title":"Starch-Gel Electrophoresis\u2014Application to the Classification of Pituitary Proteins and Polypeptides","volume":"13","author":"KA Ferguson","year":"1964","journal-title":"Metabolism"},{"key":"ref41","unstructured":"Chemical Computing Group Inc. SSW, Suite #910, Montreal, QC, Canada, H3A 2R7. Molecular Operating Environment (MOE), 2012.10. 2012."},{"key":"ref42","unstructured":"Pipeline Pilot; Accelrys Software Inc.: San Diego California U. Pipeline Pilot; Accelrys Software Inc.: San Diego California, USA. 2007."},{"issue":"7","key":"ref43","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"RA Friesner","year":"2004","journal-title":"J Med Chem"},{"issue":"Pt 10","key":"ref44","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1107\/S174430910502659X","article-title":"Expression, purification and crystallization of Trypanosoma cruzi dihydroorotate dehydrogenase complexed with orotate","volume":"61","author":"DK Inaoka","year":"2005","journal-title":"Acta Crystallogr Sect F Struct Biol Cryst Commun"},{"issue":"part A","key":"ref45","first-page":"20","article-title":"Processing of X-ray Diffraction Data Collected in Oscillation Mode","volume":"276","author":"W. Otwinowski ZaM","year":"1997","journal-title":"Methods in Enzymology"},{"issue":"Pt 12","key":"ref46","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1107\/S0907444904019158","article-title":"Coot: model-building tools for molecular graphics","volume":"60","author":"P Emsley","year":"2004","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"issue":"Pt 3","key":"ref47","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1107\/S0907444996012255","article-title":"Refinement of macromolecular structures by the maximum-likelihood method","volume":"53","author":"GN Murshudov","year":"1997","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"issue":"12","key":"ref48","doi-asserted-by":"crossref","first-page":"5899","DOI":"10.1016\/j.ejmech.2010.09.055","article-title":"Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery","volume":"45","author":"J Cheleski","year":"2010","journal-title":"Eur J Med Chem"},{"key":"ref49","article-title":"Handbook of Biochemistry and Molecular Biology FE","author":"RLLaFM MacDonald","year":"2010"},{"issue":"4","key":"ref50","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1021\/bi952168g","article-title":"The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase","volume":"35","author":"JP Davis","year":"1996","journal-title":"Biochemistry"},{"issue":"7","key":"ref51","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1021\/bi001810q","article-title":"Multiple inhibitor analysis of the brequinar and leflunomide binding sites on human dihydroorotate dehydrogenase","volume":"40","author":"JE McLean","year":"2001","journal-title":"Biochemistry"},{"issue":"7042","key":"ref52","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nature03579","article-title":"An inhibitor of Bcl-2 family proteins induces regression of solid tumours","volume":"435","author":"T Oltersdorf","year":"2005","journal-title":"Nature"},{"issue":"4","key":"ref53","doi-asserted-by":"crossref","first-page":"285","DOI":"10.3816\/CLML.2010.n.059","article-title":"Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis","volume":"10","author":"SA Parikh","year":"2010","journal-title":"Clin Lymphoma Myeloma Leuk"},{"issue":"7475","key":"ref54","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nature12595","article-title":"Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs","volume":"503","author":"RO Dror","year":"2013","journal-title":"Nature"},{"issue":"12","key":"ref55","doi-asserted-by":"crossref","first-page":"5841","DOI":"10.1021\/jm300157n","article-title":"Factors influencing the specificity of inhibitor binding to the human and malaria parasite dihydroorotate dehydrogenases","volume":"55","author":"PT Bedingfield","year":"2012","journal-title":"J Med Chem"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"W116","DOI":"10.1093\/nar\/gkl282","article-title":"CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues","volume":"34","author":"J Dundas","year":"2006","journal-title":"Nucleic Acids Res"},{"issue":"13","key":"ref57","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014a visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"J Comput Chem"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0167078","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T06:26:17Z","timestamp":1657866377000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0167078"}},"subtitle":[],"editor":[{"given":"Alexander","family":"Wlodawer","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2016,11,28]]},"references-count":57,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2016,11,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0167078","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,28]]}}}