{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T08:53:06Z","timestamp":1785228786078,"version":"3.55.0"},"reference-count":39,"publisher":"International Union of Crystallography (IUCr)","issue":"6","license":[{"start":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T00:00:00Z","timestamp":1590710400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/journals.iucr.org\/services\/copyrightpolicy.html"},{"start":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T00:00:00Z","timestamp":1590710400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/journals.iucr.org\/services\/copyrightpolicy.html#TDM"}],"funder":[{"DOI":"10.13039\/100011272","name":"Seventh Framework Programme, FP7 Health","doi-asserted-by":"publisher","award":["603240"],"award-info":[{"award-number":["603240"]}],"id":[{"id":"10.13039\/100011272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011272","name":"Seventh Framework Programme, FP7 Health","doi-asserted-by":"publisher","award":["283570"],"award-info":[{"award-number":["283570"]}],"id":[{"id":"10.13039\/100011272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["iucr.org","wiley.com","iucrj.org"],"crossmark-restriction":true},"short-container-title":["Acta Crystallogr D Struct Biol","Acta Crystallogr D","Acta Cryst D","Acta Cryst D Struct Biol","Acta Cryst Sect D","Acta Cryst Sect D Struct Biol","Acta Crystallogr Sect D","Acta Crystallogr Sect D Struct Biol","Acta Crystallogr D Biol Crystallogr","Acta Cryst D Biol Cryst"],"accepted":{"date-parts":[[2020,4,6]]},"published-print":{"date-parts":[[2020,6,1]]},"abstract":"<jats:p>The protozoan parasite <jats:italic>Trypanosoma brucei<\/jats:italic> is the etiological agent of human African trypanosomiasis (HAT). HAT, together with other neglected tropical diseases, causes serious health and economic issues, especially in tropical and subtropical areas. The classical antifolates targeting dihydrofolate reductase (DHFR) are ineffective towards trypanosomatid parasites owing to a metabolic bypass by the expression of pteridine reductase 1 (PTR1). The combined inhibition of PTR1 and DHFR activities in <jats:italic>Trypanosoma<\/jats:italic> parasites represents a promising strategy for the development of new effective treatments for HAT. To date, only monocyclic and bicyclic aromatic systems have been proposed as inhibitors of <jats:italic>T. brucei<\/jats:italic> PTR1 (<jats:italic>Tb<\/jats:italic>PTR1); nevertheless, the size of the catalytic cavity allows the accommodation of expanded molecular cores. Here, an innovative tricyclic-based compound has been explored as a <jats:italic>Tb<\/jats:italic>PTR1-targeting molecule and its potential application for the development of a new class of PTR1 inhibitors has been evaluated. 2,4-Diaminopyrimido[4,5-<jats:italic>b<\/jats:italic>]indol-6-ol (<jats:bold>1<\/jats:bold>) was designed and synthesized, and was found to be effective in blocking <jats:italic>Tb<\/jats:italic>PTR1 activity, with a <jats:italic>K<\/jats:italic>\n                  <jats:sub>i<\/jats:sub> in the low-micromolar range. The binding mode of <jats:bold>1<\/jats:bold> was clarified through the structural characterization of its ternary complex with <jats:italic>Tb<\/jats:italic>PTR1 and the cofactor NADP(H), which was determined to 1.30\u2005\u00c5 resolution. The compound adopts a substrate-like orientation inside the cavity that maximizes the binding contributions of hydrophobic and hydrogen-bond interactions. The binding mode of <jats:bold>1<\/jats:bold> was compared with those of previously reported bicyclic inhibitors, providing new insights for the design of innovative tricyclic-based molecules targeting <jats:italic>Tb<\/jats:italic>PTR1.<\/jats:p>","DOI":"10.1107\/s2059798320004891","type":"journal-article","created":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T13:57:06Z","timestamp":1590760626000},"page":"558-564","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":11,"title":["High-resolution crystal structure of <i>Trypanosoma brucei<\/i> pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor"],"prefix":"10.1107","volume":"76","author":[{"given":"Giacomo","family":"Landi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0382-7479","authenticated-orcid":true,"given":"Pasquale","family":"Linciano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-5528","authenticated-orcid":true,"given":"Giusy","family":"Tassone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0443-5402","authenticated-orcid":true,"given":"Maria Paola","family":"Costi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4824-7478","authenticated-orcid":true,"given":"Stefano","family":"Mangani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2574-3911","authenticated-orcid":true,"given":"Cecilia","family":"Pozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"329","published-online":{"date-parts":[[2020,5,29]]},"reference":[{"key":"ag5036_bb1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/cid\/cis886","volume":"56","author":"Alirol","year":"2013","journal-title":"Clin. 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