Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs
Autor(a) principal: | |
---|---|
Data de Publicação: | 2023 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/1822/86973 |
Resumo: | The search for Golgi a-mannosidase II (GMII) potent and specific inhibitors has been a focus of many studies for the past three decades since this enzyme is a key target for cancer treatment. a-Mannosidases, such as those from Drosophila melanogaster or Jack bean, have been used as functional models of the human Golgi a-mannosidase II (hGMII) because mammalian mannosidases are difficult to purify and characterize experimentally. Meanwhile, computational studies have been seen as privileged tools able to explore assertive solutions to specific enzymes, providing molecular details of these macromolecules, their protonation states and their interactions. Thus, modelling techniques can successfully predict hGMII 3D structure with high confidence, speeding up the development of new hits. In this study, Drosophila melanogaster Golgi mannosidase II (dGMII) and a novel human model, developed in silico and equilibrated via molecular dynamics simulations, were both opposed for docking. Our findings highlight that the design of novel inhibitors should be carried out considering the human model’s characteristics and the enzyme operating pH. A reliable model is evidenced, showing a good correlation between Ki/IC50 experimental data and theoretical DGbinding estimations in GMII, opening the possibility of optimizing the rational drug design of new derivatives |
id |
RCAP_15b816f8658246da7e1326bf707a0a72 |
---|---|
oai_identifier_str |
oai:repositorium.sdum.uminho.pt:1822/86973 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHsGolgi a-mannosidase IIIminosugarsMolecular dynamics simulationsMolecular dockingpHStructural assessmentInhibitorsCiências Naturais::Ciências QuímicasSaúde de qualidadeThe search for Golgi a-mannosidase II (GMII) potent and specific inhibitors has been a focus of many studies for the past three decades since this enzyme is a key target for cancer treatment. a-Mannosidases, such as those from Drosophila melanogaster or Jack bean, have been used as functional models of the human Golgi a-mannosidase II (hGMII) because mammalian mannosidases are difficult to purify and characterize experimentally. Meanwhile, computational studies have been seen as privileged tools able to explore assertive solutions to specific enzymes, providing molecular details of these macromolecules, their protonation states and their interactions. Thus, modelling techniques can successfully predict hGMII 3D structure with high confidence, speeding up the development of new hits. In this study, Drosophila melanogaster Golgi mannosidase II (dGMII) and a novel human model, developed in silico and equilibrated via molecular dynamics simulations, were both opposed for docking. Our findings highlight that the design of novel inhibitors should be carried out considering the human model’s characteristics and the enzyme operating pH. A reliable model is evidenced, showing a good correlation between Ki/IC50 experimental data and theoretical DGbinding estimations in GMII, opening the possibility of optimizing the rational drug design of new derivativesThis study was supported by the Portuguese Foundation for Science and Technology (FCT) for funding the PhD fellowship SFRH/BD/150695/2020 assigned to Artem Drogalin by the SPQ within the international year of the periodic table. Thanks are due to FCT and FEDER (European Fund for Regional Development)-COMPETE-QRENEU for financial support through the Chemistry Research Centre of the University of Minho (Ref. CQ/UM (UID/QUI/00686/2020)). Castro thanks FCT under the scope of the strategic funding of UIDB/04469/2020 unit, and by LABBELS – Associate Laboratory in Biotechnology, Bioengineering and Microelectromechanical Systems, LA/P/0029/2020. This research was developed with the support of comput ing facilities provided by the Project Search-ON2 must include in their publi cations (papers and thesis) the following reference: “Search-ON2: Revitalization of HPC infrastructure of UMinho” (NORTE-07-0162-FEDER 000086), co-funded by the North Portugal Regional Operational Programme(ON.2 – O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF)Taylor & FrancisUniversidade do MinhoDrogalin, ArtemMonteiro, Luís S.Alves, Maria José ChãoCastro, Tarsila Gabriel20232023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/86973eng0739-11021538-025410.1080/07391102.2023.2209184https://www.tandfonline.com/doi/full/10.1080/07391102.2023.2209184info: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:RCAAP2023-12-23T01:38:53Zoai:repositorium.sdum.uminho.pt:1822/86973Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:39:03.620464Repositório 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 |
Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs |
title |
Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs |
spellingShingle |
Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs Drogalin, Artem Golgi a-mannosidase II Iminosugars Molecular dynamics simulations Molecular docking pH Structural assessment Inhibitors Ciências Naturais::Ciências Químicas Saúde de qualidade |
title_short |
Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs |
title_full |
Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs |
title_fullStr |
Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs |
title_full_unstemmed |
Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs |
title_sort |
Golgi α-mannosidase: opposing structures of Drosophila melanogaster and novel human model using molecular dynamics simulations and docking at different pHs |
author |
Drogalin, Artem |
author_facet |
Drogalin, Artem Monteiro, Luís S. Alves, Maria José Chão Castro, Tarsila Gabriel |
author_role |
author |
author2 |
Monteiro, Luís S. Alves, Maria José Chão Castro, Tarsila Gabriel |
author2_role |
author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Drogalin, Artem Monteiro, Luís S. Alves, Maria José Chão Castro, Tarsila Gabriel |
dc.subject.por.fl_str_mv |
Golgi a-mannosidase II Iminosugars Molecular dynamics simulations Molecular docking pH Structural assessment Inhibitors Ciências Naturais::Ciências Químicas Saúde de qualidade |
topic |
Golgi a-mannosidase II Iminosugars Molecular dynamics simulations Molecular docking pH Structural assessment Inhibitors Ciências Naturais::Ciências Químicas Saúde de qualidade |
description |
The search for Golgi a-mannosidase II (GMII) potent and specific inhibitors has been a focus of many studies for the past three decades since this enzyme is a key target for cancer treatment. a-Mannosidases, such as those from Drosophila melanogaster or Jack bean, have been used as functional models of the human Golgi a-mannosidase II (hGMII) because mammalian mannosidases are difficult to purify and characterize experimentally. Meanwhile, computational studies have been seen as privileged tools able to explore assertive solutions to specific enzymes, providing molecular details of these macromolecules, their protonation states and their interactions. Thus, modelling techniques can successfully predict hGMII 3D structure with high confidence, speeding up the development of new hits. In this study, Drosophila melanogaster Golgi mannosidase II (dGMII) and a novel human model, developed in silico and equilibrated via molecular dynamics simulations, were both opposed for docking. Our findings highlight that the design of novel inhibitors should be carried out considering the human model’s characteristics and the enzyme operating pH. A reliable model is evidenced, showing a good correlation between Ki/IC50 experimental data and theoretical DGbinding estimations in GMII, opening the possibility of optimizing the rational drug design of new derivatives |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023 2023-01-01T00:00:00Z |
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://hdl.handle.net/1822/86973 |
url |
https://hdl.handle.net/1822/86973 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0739-1102 1538-0254 10.1080/07391102.2023.2209184 https://www.tandfonline.com/doi/full/10.1080/07391102.2023.2209184 |
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.publisher.none.fl_str_mv |
Taylor & Francis |
publisher.none.fl_str_mv |
Taylor & Francis |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799133651454132224 |