{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T03:48:30Z","timestamp":1788320910427,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T00:00:00Z","timestamp":1699574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The parasites Trypanosoma brucei (Tb) and Leishmania major (Lm) cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living in tropical to subtropical climates fall victim to these illnesses\u2019 health threats. The parasites\u2019 frequent drug resistance and widely spread natural reservoirs heavily impede disease prevention and treatment. Due to pteridine auxotrophy, trypanosomatid parasites have developed a peculiar enzyme system consisting of dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) to support cell survival. Extending our previous studies, we conducted a comparative study of the T. brucei (TbDHFR, TbPTR1) and L. major (LmDHFR, LmPTR1) enzymes to identify lead structures with a dual inhibitory effect. A pharmacophore-based in silico screening of three natural product databases (approximately 4880 compounds) was performed to preselect possible inhibitors. Building on the in silico results, the inhibitory potential of promising compounds was verified in vitro against the recombinant DHFR and PTR1 of both parasites using spectrophotometric enzyme assays. Twelve compounds were identified as dual inhibitors against the Tb enzymes (0.2 \u03bcM &lt; IC50 &lt; 85.1 \u03bcM) and ten against the respective Lm enzymes (0.6 \u03bcM &lt; IC50 &lt; 84.5 \u03bcM). These highly promising results may represent the starting point for the future development of new leads and drugs utilizing the trypanosomatid pteridine metabolism as a target.<\/jats:p>","DOI":"10.3390\/molecules28227526","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T02:46:47Z","timestamp":1699843607000},"page":"7526","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In Silico and In Vitro Search for Dual Inhibitors of the Trypanosoma brucei and Leishmania major Pteridine Reductase 1 and Dihydrofolate Reductase"],"prefix":"10.3390","volume":"28","author":[{"given":"Katharina","family":"Possart","sequence":"first","affiliation":[{"name":"University of Muenster, Institute for Pharmaceutical Biology and Phytochemistry (IPBP), PharmaCampus, Corrensstrasse 48, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian C.","family":"Herrmann","sequence":"additional","affiliation":[{"name":"University of Muenster, Institute for Pharmaceutical Biology and Phytochemistry (IPBP), PharmaCampus, Corrensstrasse 48, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0666-2676","authenticated-orcid":false,"given":"Joachim","family":"Jose","sequence":"additional","affiliation":[{"name":"University of Muenster, Institute of Pharmaceutical and Medicinal Chemistry, PharmaCampus, Corrensstrasse 48, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-9705","authenticated-orcid":false,"given":"Thomas J.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"University of Muenster, Institute for Pharmaceutical Biology and Phytochemistry (IPBP), PharmaCampus, Corrensstrasse 48, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,10]]},"reference":[{"key":"ref_1","unstructured":"(2023, June 22). 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