{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:47:06Z","timestamp":1791229626587,"version":"4.1.0"},"reference-count":68,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2014,4,30]],"date-time":"2014-04-30T00:00:00Z","timestamp":1398816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure\u2010based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small\u2010molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so\u2010called \u201cmepacrine binding site\u201d. The binding conformation and potency of the inhibitors varied for TR from\n                    <jats:italic>Trypanosoma brucei<\/jats:italic>\n                    and\n                    <jats:italic>T.\u2005cruzi<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1002\/cmdc.201402032","type":"journal-article","created":{"date-parts":[[2014,4,30]],"date-time":"2014-04-30T16:29:26Z","timestamp":1398875366000},"page":"1880-1891","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Binding to Large Enzyme Pockets: Small\u2010Molecule Inhibitors of Trypanothione Reductase"],"prefix":"10.1002","volume":"9","author":[{"given":"Elke","family":"Persch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Bryson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickolay K.","family":"Todoroff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Eberle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Thelemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Dirdjaja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Kaiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Derbani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reto","family":"Brun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisbert","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emil F.","family":"Pai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Luise","family":"Krauth\u2010Siegel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Diederich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,4,30]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001007"},{"key":"e_1_2_6_2_2","unstructured":"Report of a WHO meeting on elimination of African trypanosomiasis (Trypanosoma brucei gambiense) World Health Organization Geneva 2013."},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(13)70191-9"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/1756-3305-1-3"},{"key":"e_1_2_6_5_2","unstructured":"Research Priorities for Chagas Disease Human African Trypanosomiasis and Leishmaniasis WHO Technical Report Series No. 975 2012."},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707354"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200300639"},{"key":"e_1_2_6_7_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200300639"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568026023393048"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867311320210005"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3883489"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/273120a0"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00360a007"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1992.tb01766.x"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00385a011"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0968-0896(96)00120-4"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(99)80011-2"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1039\/b806371k"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201000420"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200900097"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200900098"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(93)81501-P"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(96)00423-1"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0928-0987(99)00077-9"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm990386s"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403187200"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201300176"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(00)00471-6"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.3109\/14756366.2011.604319"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00124456"},{"key":"e_1_2_6_30_2","unstructured":"Residues marked with a prime belong to the second subunit of the homodimeric enzyme."},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(91)90531-W"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00813749"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm000156"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm050819t"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00894-009-0468-3"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21538"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201200512"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201102571"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201108731"},{"key":"e_1_2_6_39_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201108731"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.039255"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-1989-27156"},{"key":"e_1_2_6_42_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo048541k"},{"key":"e_1_2_6_43_2","first-page":"599","volume":"39","author":"Iorio M. A.","year":"1984","journal-title":"Farmaco Sci."},{"key":"e_1_2_6_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0134(199601)24:1<73::AID-PROT5>3.0.CO;2-P"},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm200312v"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.19.8769"},{"key":"e_1_2_6_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(95)80037-9"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0897"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21082"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2011.672633"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/9783527670383.ch21"},{"key":"e_1_2_6_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1993.tb17734.x"},{"key":"e_1_2_6_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.09.077"},{"key":"e_1_2_6_54_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2860009"},{"key":"e_1_2_6_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560050107"},{"key":"e_1_2_6_56_2","unstructured":"The PyMOL Molecular Graphics System Version 1.5.0.4 Schr\u00f6dinger LLC 2010."},{"key":"e_1_2_6_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)89502-8"},{"key":"e_1_2_6_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2009.09.002"},{"key":"e_1_2_6_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-6851(91)90231-T"},{"key":"e_1_2_6_60_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4020-6316-9_4"},{"key":"e_1_2_6_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(97)76066-X"},{"key":"e_1_2_6_62_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889807021206"},{"key":"e_1_2_6_63_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444998003254"},{"key":"e_1_2_6_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.406"},{"key":"e_1_2_6_65_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444996012255"},{"key":"e_1_2_6_66_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909052925"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcmdc.201402032","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201402032","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T15:56:20Z","timestamp":1760284580000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.201402032"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,30]]},"references-count":68,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2014,8]]}},"alternative-id":["10.1002\/cmdc.201402032"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.201402032","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,30]]},"assertion":[{"value":"2014-02-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-04-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}