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Molecules 2018, 23(4), 772; https://doi.org/10.3390/molecules23040772

In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum

1
Center of Multidisciplinary Research, Institute of Nuclear Sciences “Vinča”, University of Belgrade, 11001 Belgrade, Serbia
2
National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
3
i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto and IBMC-Institute for Molecular and Cell Biology, 4099-002 Porto, Portugal
4
ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4099-002 Porto, Portugal
5
Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 1099-085 Oeiras, Portugal
6
University of Lisbon, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Campo Grande, C8, 1749-016 Lisboa, Portugal
*
Authors to whom correspondence should be addressed.
Received: 4 March 2018 / Revised: 21 March 2018 / Accepted: 26 March 2018 / Published: 27 March 2018
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Abstract

There is an urgent need for the discovery of new antileishmanial drugs with a new mechanism of action. Type 2 NADH dehydrogenase from Leishmania infantum (LiNDH2) is an enzyme of the parasite’s respiratory system, which catalyzes the electron transfer from NADH to ubiquinone without coupled proton pumping. In previous studies of the related NADH: ubiquinone oxidoreductase crystal structure from Saccharomyces cerevisiae, two ubiquinone-binding sites (UQI and UQII) were identified and shown to play an important role in the NDH-2-catalyzed oxidoreduction reaction. Based on the available structural data, we developed a three-dimensional structural model of LiNDH2 using homology detection methods and performed an in silico virtual screening campaign to search for potential inhibitors targeting the LiNDH2 ubiquinone-binding site 1—UQI. Selected compounds displaying favorable properties in the computational screening experiments were assayed for inhibitory activity in the structurally similar recombinant NDH-2 from S. aureus and leishmanicidal activity was determined in the wild-type axenic amastigotes and promastigotes of L. infantum. The identified compound, a substituted 6-methoxy-quinalidine, showed promising nanomolar leishmanicidal activity on wild-type axenic promastigotes and amastigotes of L. infantum and the potential for further development. View Full-Text
Keywords: Leishmania infantum alternative NADH dehydrogenase (LiNDH2); antileishmanial drugs; Leishmania infantum virtual screening; drug design Leishmania infantum alternative NADH dehydrogenase (LiNDH2); antileishmanial drugs; Leishmania infantum virtual screening; drug design
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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).

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Stevanović, S.; Perdih, A.; Senćanski, M.; Glišić, S.; Duarte, M.; Tomás, A.M.; Sena, F.V.; Sousa, F.M.; Pereira, M.M.; Solmajer, T. In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum. Molecules 2018, 23, 772.

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