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

Autor: Stevanović S; Center of Multidisciplinary Research, Institute of Nuclear Sciences 'Vinča', University of Belgrade, 11001 Belgrade, Serbia. sstevanovic@vin.bg.ac.rs., Perdih A; National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia. andrej.perdih@ki.si., Senćanski M; Center of Multidisciplinary Research, Institute of Nuclear Sciences 'Vinča', University of Belgrade, 11001 Belgrade, Serbia. sencanski@vin.bg.ac.rs., Glišić S; Center of Multidisciplinary Research, Institute of Nuclear Sciences 'Vinča', University of Belgrade, 11001 Belgrade, Serbia. sanja@vinca.rs., Duarte M; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto and IBMC-Institute for Molecular and Cell Biology, 4099-002 Porto, Portugal. mduarte@ibmc.up.pt., Tomás AM; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto and IBMC-Institute for Molecular and Cell Biology, 4099-002 Porto, Portugal. atomas@ibmc.up.pt.; ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4099-002 Porto, Portugal. atomas@ibmc.up.pt., Sena FV; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 1099-085 Oeiras, Portugal. fsena@itqb.unl.pt., Sousa FM; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 1099-085 Oeiras, Portugal. filipe.sousa@itqb.unl.pt., Pereira MM; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 1099-085 Oeiras, Portugal. mpereira@itqb.unl.pt.; University of Lisbon, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Campo Grande, C8,1749-016 Lisboa, Portugal. mpereira@itqb.unl.pt., Solmajer T; National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia. tom.solmajer@ki.si.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2018 Mar 27; Vol. 23 (4). Date of Electronic Publication: 2018 Mar 27.
DOI: 10.3390/molecules23040772
Abstrakt: 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 ( Li NDH2) 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 (UQ I and UQ II ) 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 Li NDH2 using homology detection methods and performed an in silico virtual screening campaign to search for potential inhibitors targeting the Li NDH2 ubiquinone-binding site 1-UQ I . 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.
Competing Interests: The authors declare no conflicts of interest.
Databáze: MEDLINE
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