In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://doi.org/10.3390/molecules23040772 |
Resumo: | 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. |
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In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantumAntileishmanial drugsDrug designLeishmania infantum alternative NADH dehydrogenase (LiNDH2)Leishmania infantum virtual screeningAnalytical ChemistryChemistry (miscellaneous)Molecular MedicinePharmaceutical ScienceDrug DiscoveryPhysical and Theoretical ChemistryOrganic ChemistryThere 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.Instituto de Tecnologia Química e Biológica António Xavier (ITQB)RUNStevanović, StrahinjaPerdih, AndrejSenćanski, MilanGli ić, SanjaDuarte, MargaridaTomás, Ana M.Sena, Filipa V.Sousa, Filipe M.Pereira, Manuela M.Solmajer, Tom2019-04-24T22:21:16Z2018-01-012018-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://doi.org/10.3390/molecules23040772engPURE: 6323459http://www.scopus.com/inward/record.url?scp=85044729355&partnerID=8YFLogxKhttps://doi.org/10.3390/molecules23040772info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T04:31:58Zoai:run.unl.pt:10362/67611Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:34:38.843238Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum |
title |
In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum |
spellingShingle |
In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum Stevanović, Strahinja Antileishmanial drugs Drug design Leishmania infantum alternative NADH dehydrogenase (LiNDH2) Leishmania infantum virtual screening Analytical Chemistry Chemistry (miscellaneous) Molecular Medicine Pharmaceutical Science Drug Discovery Physical and Theoretical Chemistry Organic Chemistry |
title_short |
In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum |
title_full |
In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum |
title_fullStr |
In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum |
title_full_unstemmed |
In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum |
title_sort |
In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum |
author |
Stevanović, Strahinja |
author_facet |
Stevanović, Strahinja Perdih, Andrej Senćanski, Milan Gli ić, Sanja Duarte, Margarida Tomás, Ana M. Sena, Filipa V. Sousa, Filipe M. Pereira, Manuela M. Solmajer, Tom |
author_role |
author |
author2 |
Perdih, Andrej Senćanski, Milan Gli ić, Sanja Duarte, Margarida Tomás, Ana M. Sena, Filipa V. Sousa, Filipe M. Pereira, Manuela M. Solmajer, Tom |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Instituto de Tecnologia Química e Biológica António Xavier (ITQB) RUN |
dc.contributor.author.fl_str_mv |
Stevanović, Strahinja Perdih, Andrej Senćanski, Milan Gli ić, Sanja Duarte, Margarida Tomás, Ana M. Sena, Filipa V. Sousa, Filipe M. Pereira, Manuela M. Solmajer, Tom |
dc.subject.por.fl_str_mv |
Antileishmanial drugs Drug design Leishmania infantum alternative NADH dehydrogenase (LiNDH2) Leishmania infantum virtual screening Analytical Chemistry Chemistry (miscellaneous) Molecular Medicine Pharmaceutical Science Drug Discovery Physical and Theoretical Chemistry Organic Chemistry |
topic |
Antileishmanial drugs Drug design Leishmania infantum alternative NADH dehydrogenase (LiNDH2) Leishmania infantum virtual screening Analytical Chemistry Chemistry (miscellaneous) Molecular Medicine Pharmaceutical Science Drug Discovery Physical and Theoretical Chemistry Organic Chemistry |
description |
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. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-01-01 2018-01-01T00:00:00Z 2019-04-24T22:21:16Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://doi.org/10.3390/molecules23040772 |
url |
https://doi.org/10.3390/molecules23040772 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
PURE: 6323459 http://www.scopus.com/inward/record.url?scp=85044729355&partnerID=8YFLogxK https://doi.org/10.3390/molecules23040772 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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