دورية أكاديمية
In Silico and In Vitro Search for Dual Inhibitors of the Trypanosoma brucei and Leishmania major Pteridine Reductase 1 and Dihydrofolate Reductase
| العنوان: | In Silico and In Vitro Search for Dual Inhibitors of the Trypanosoma brucei and Leishmania major Pteridine Reductase 1 and Dihydrofolate Reductase |
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| المؤلفون: | Katharina Possart, Fabian C. Herrmann, Joachim Jose, Thomas J. Schmidt |
| المصدر: | Molecules, Vol 28, Iss 22, p 7526 (2023) |
| بيانات النشر: | MDPI AG, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Organic chemistry |
| مصطلحات موضوعية: | Trypanosoma brucei, Leishmania major, human African trypanosomiasis, cutaneous leishmaniasis, pteridine reductase 1 inhibitor, dihydrofolate reductase inhibitor, Organic chemistry, QD241-441 |
| الوصف: | 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’ health threats. The parasites’ 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 μM < IC50 < 85.1 μM) and ten against the respective Lm enzymes (0.6 μM < IC50 < 84.5 μM). 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1420-3049 87093197 |
| Relation: | https://www.mdpi.com/1420-3049/28/22/7526; https://doaj.org/toc/1420-3049 |
| DOI: | 10.3390/molecules28227526 |
| URL الوصول: | https://doaj.org/article/cbaacb37f326440b8709319782792014 |
| رقم الأكسشن: | edsdoj.baacb37f326440b8709319782792014 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14203049 87093197 |
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| DOI: | 10.3390/molecules28227526 |