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

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2018
molecules-23-00772-v2.pdf (44.29Mb)
Authors
Stevanović, Strahinja
Perdih, Andrej
Senćanski, Milan V.
Glišić, Sanja
Duarte, Margarida
Tomas, Ana
Sena, Filipa
Sousa, Filipe
Pereira, Manuela M.
Šolmajer, Tom
Article (Published version)
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© 2018 by the Authors
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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.

Keywords:
Leishmania infantum alternative NADH dehydrogenase / Leishmania infantum virtual screening / antileishmanial drugs / drug design
Source:
Molecules, 2018, 23, 4, 772-
Funding / projects:
  • Application of the EIIP/ISM bioinformatics platform in discovery of novel therapeutic targets and potential therapeutic molecules (RS-173001)
  • Ministry of Higher Education, Science and Technology of the Republic of Slovenia (P1-0012)
  • Fundacao para a Ciencia e a Tecnologia (PD/BD/113985/2015)
  • Fundacao para a Ciencia e a Tecnologia (PD/BD/128213/2016)
  • Fundacao para a Ciencia e a Tecnologia (PD/00133/2012)
  • Fundacao para a Ciencia e a Tecnologia FCT (IF/01507/2015)
  • Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL, through the European Regional Development Fund (FEDER) (Norte-01-0145-FEDER-000012)
  • COST Action "Targeted chemotherapy towards diseases caused by endoparasites" (CM1307)
  • COST Action Understanding Movement and Mechanism in Molecular Machines (CM1306)

DOI: 10.3390/molecules23040772

ISSN: 1420-3049

PubMed: 29584709

WoS: 000434717300064

Scopus: 2-s2.0-85044729355
[ Google Scholar ]
15
13
URI
http://www.mdpi.com/1420-3049/23/4/772
https://vinar.vin.bg.ac.rs/handle/123456789/7774
Collections
  • Radovi istraživača
Institution/Community
Vinča
TY  - JOUR
AU  - Stevanović, Strahinja
AU  - Perdih, Andrej
AU  - Senćanski, Milan V.
AU  - Glišić, Sanja
AU  - Duarte, Margarida
AU  - Tomas, Ana
AU  - Sena, Filipa
AU  - Sousa, Filipe
AU  - Pereira, Manuela M.
AU  - Šolmajer, Tom
PY  - 2018
UR  - http://www.mdpi.com/1420-3049/23/4/772
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/7774
AB  - 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.
T2  - Molecules
T1  - In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum
VL  - 23
IS  - 4
SP  - 772
DO  - 10.3390/molecules23040772
ER  - 
@article{
author = "Stevanović, Strahinja and Perdih, Andrej and Senćanski, Milan V. and Glišić, Sanja and Duarte, Margarida and Tomas, Ana and Sena, Filipa and Sousa, Filipe and Pereira, Manuela M. and Šolmajer, Tom",
year = "2018",
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.",
journal = "Molecules",
title = "In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum",
volume = "23",
number = "4",
pages = "772",
doi = "10.3390/molecules23040772"
}
Stevanović, S., Perdih, A., Senćanski, M. V., Glišić, S., Duarte, M., Tomas, A., Sena, F., Sousa, F., Pereira, M. M.,& Šolmajer, T.. (2018). In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum. in Molecules, 23(4), 772.
https://doi.org/10.3390/molecules23040772
Stevanović S, Perdih A, Senćanski MV, Glišić S, Duarte M, Tomas A, Sena F, Sousa F, Pereira MM, Šolmajer T. In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum. in Molecules. 2018;23(4):772.
doi:10.3390/molecules23040772 .
Stevanović, Strahinja, Perdih, Andrej, Senćanski, Milan V., Glišić, Sanja, Duarte, Margarida, Tomas, Ana, Sena, Filipa, Sousa, Filipe, Pereira, Manuela M., Šolmajer, Tom, "In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum" in Molecules, 23, no. 4 (2018):772,
https://doi.org/10.3390/molecules23040772 . .

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