Next Article in Journal
Synthesis of Benzyl Acetate Catalyzed by Lipase Immobilized in Nontoxic Chitosan-Polyphosphate Beads
Previous Article in Journal
Thymbra capitata (L.) Cav. and Rosmarinus officinalis (L.) Essential Oils: In Vitro Effects and Toxicity on Swine Spermatozoa
Previous Article in Special Issue
In Vivo and In Vitro Activities and ADME-Tox Profile of a Quinolizidine-Modified 4-Aminoquinoline: A Potent Anti-P. falciparum and Anti-P. vivax Blood-Stage Antimalarial
Article Menu

Export Article

Open AccessArticle
Molecules 2017, 22(12), 2166; doi:10.3390/molecules22122166

In Silico Identification and In Vitro Evaluation of Natural Inhibitors of Leishmania major Pteridine Reductase I

1
Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Muenster, PharmaCampus, Corrensstrasse 48, D-48149 Muenster, Germany
2
Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, PharmaCampus, Correnstrasse 48, D-48149 Muenster, Germany
3
Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy
4
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, 53100 Siena, Italy
*
Author to whom correspondence should be addressed.
Received: 14 November 2017 / Revised: 30 November 2017 / Accepted: 5 December 2017 / Published: 6 December 2017
View Full-Text   |   Download PDF [13257 KB, uploaded 6 December 2017]   |  

Abstract

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’ 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 µM. The IC50 values were determined for the six NPs that inhibited the target enzyme by more than 50% at 50 µM, with sophoraflavanone G being the most active compound tested (IC50 = 19.2 µM). 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. View Full-Text
Keywords: Leishmania major; cutaneous Leishmaniasis; pteridine reductase I inhibitor; natural product; in silico screening Leishmania major; cutaneous Leishmaniasis; pteridine reductase I inhibitor; natural product; in silico screening
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Herrmann, F.C.; Sivakumar, N.; Jose, J.; Costi, M.P.; Pozzi, C.; Schmidt, T.J. In Silico Identification and In Vitro Evaluation of Natural Inhibitors of Leishmania major Pteridine Reductase I. Molecules 2017, 22, 2166.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top