In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum
Autori
Stevanović, StrahinjaPerdih, Andrej
Senćanski, Milan V.
Glišić, Sanja
Duarte, Margarida
Tomas, Ana
Sena, Filipa
Sousa, Filipe
Pereira, Manuela M.
Šolmajer, Tom
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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.
Ključne reči:
Leishmania infantum alternative NADH dehydrogenase / Leishmania infantum virtual screening / antileishmanial drugs / drug designIzvor:
Molecules, 2018, 23, 4, 772-Finansiranje / projekti:
- Primena EIIP/ISM bioinformatičke platforme u otkrivanju novih terapeutskih targeta i potencijalnih terapeutskih molekula (RS-MESTD-Basic Research (BR or ON)-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
Kolekcije
Institucija/grupa
VinčaTY - 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 . .