{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:47:51Z","timestamp":1791895671097,"version":"4.3.4"},"reference-count":25,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2017,12,6]],"date-time":"2017-12-06T00:00:00Z","timestamp":1512518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European union, 7th framework program","award":["603240"],"award-info":[{"award-number":["603240"]}]},{"DOI":"10.13039\/501100000780","name":"European union","doi-asserted-by":"publisher","award":["COST CM1307"],"award-info":[{"award-number":["COST CM1307"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In a continuation of our computational efforts to find new natural inhibitors of a variety of target enzymes from parasites causing neglected tropical diseases (NTDs), we now report on 15 natural products (NPs) that we have identified as inhibitors of Leishmania major pteridine reductase I (LmPTR1) through a combination of in silico and in vitro investigations. Pteridine reductase (PTR1) is an enzyme of the trypanosomatid parasites\u2019 peculiar folate metabolism, and has previously been validated as a drug target. Initially, pharmacophore queries were created based on four 3D structures of LmPTR1 using co-crystallized known inhibitors as templates. Each of the pharmacophore queries was used to virtually screen a database of 1100 commercially available natural products. The resulting hits were submitted to molecular docking analyses in the substrate binding site of the respective protein structures used for the pharmacophore design. This approach led to the in silico identification of a total of 18 NPs with predicted binding affinity to LmPTR1. These compounds were subsequently tested in vitro for inhibitory activity towards recombinant LmPTR1 in a spectrophotometric inhibition assay. Fifteen out of the 18 tested compounds (hit rate = 83%) showed significant inhibitory activity against LmPTR1 when tested at a concentration of 50 \u00b5M. The IC50 values were determined for the six NPs that inhibited the target enzyme by more than 50% at 50 \u00b5M, with sophoraflavanone G being the most active compound tested (IC50 = 19.2 \u00b5M). The NPs identified and evaluated in the present study may represent promising lead structures for the further rational drug design of more potent inhibitors against LmPTR1.<\/jats:p>","DOI":"10.3390\/molecules22122166","type":"journal-article","created":{"date-parts":[[2017,12,6]],"date-time":"2017-12-06T11:29:36Z","timestamp":1512559776000},"page":"2166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["In Silico Identification and In Vitro Evaluation of Natural Inhibitors of Leishmania major Pteridine Reductase I"],"prefix":"10.3390","volume":"22","author":[{"given":"Fabian","family":"Herrmann","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Muenster, PharmaCampus, Corrensstrasse 48, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirina","family":"Sivakumar","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Muenster, 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":"Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, PharmaCampus, Correnstrasse 48, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Costi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2574-3911","authenticated-orcid":false,"given":"Cecilia","family":"Pozzi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-9705","authenticated-orcid":false,"given":"Thomas","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Muenster, PharmaCampus, Corrensstrasse 48, D-48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1055\/s-0033-1351916","article-title":"In silico screening of natural product databases reveals new potential leads against neglected diseases","volume":"79","author":"Herrmann","year":"2013","journal-title":"Planta Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16154","DOI":"10.3390\/molecules200916154","article-title":"In Silico identification and in vitro activity of novel natural inhibitors of Trypanosoma brucei glyceraldehyde-3-phosphate-dehydrogenase","volume":"20","author":"Herrmann","year":"2015","journal-title":"Molecules"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1017\/S0031182097001133","article-title":"New approaches to Leishmania chemotherapy: Pteridine reductase 1 (PTR1) as target modulator of antifolate sensitivity","volume":"114","author":"Nare","year":"1997","journal-title":"Parasitology"},{"key":"ref_4","unstructured":"(2017, August 02). 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