Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibition

Diabetes mellitus (DM) stands as a significant global health challenge, ranking third among causes of mortality worldwide. Despite extensive endeavors, effective treatments for diabetes remain elusive. Alpha-glucosidase, a pivotal enzyme in glycoprotein metabolism regulation, emerges as a promising...

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Autores: Malik, Saima, Lodhi, Muhammad Arif, Ayaz, Sultan, Ullah, Zakir
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/371712
Acceso en línea:http://hdl.handle.net/10261/371712
https://api.elsevier.com/content/abstract/scopus_id/85189030393
Access Level:acceso abierto
Palabra clave:Lysosomal α-glucosidase (GAA)
Molecular docking
Molecular dynamic simulation
PCA
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spelling Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibitionIdentification of promising Lysosomal α-Glucosidase (rhGAA) inhibitors: A mechanistic exploration through pharmacophore based virtual screening, molecular docking coupled with Molecular dynamic simulationMalik, SaimaLodhi, Muhammad ArifAyaz, SultanUllah, ZakirLysosomal α-glucosidase (GAA)Molecular dockingMolecular dynamic simulationPCADiabetes mellitus (DM) stands as a significant global health challenge, ranking third among causes of mortality worldwide. Despite extensive endeavors, effective treatments for diabetes remain elusive. Alpha-glucosidase, a pivotal enzyme in glycoprotein metabolism regulation, emerges as a promising therapeutic target for mitigating postprandial hyperglycemia, a hallmark of diabetes. In this study, we employed advanced computational methodologies to identify inhibitors of lysosomal α-glucosidase. Leveraging pharmacophore-based virtual screening of a vast library of drug-like molecules, we unearthed 161 potential inhibitors capable of binding within the enzyme's active pocket. Subsequent molecular docking simulations yielded five lead molecules exhibiting robust binding affinities and favorable interaction profiles with critical catalytic residues. Further analysis through molecular dynamics simulations provided crucial insights into the stability and conformational dynamics of the inhibitor-enzyme complexes. Notably, certain residues emerged as pivotal for the retention of inhibitors within the active site. Our findings underscore the potential of LIG1-LIG5 as promising inhibitors against lysosomal α-glucosidase, presenting novel avenues for the development of effective diabetes therapeutics. This research enriches our understanding of the molecular underpinnings of diabetes treatment, facilitating targeted drug development strategies in the quest for improved patient outcomes.With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2023-001263-S).Peer reviewedElsevierAgencia Estatal de Investigación (España)Ullah, Zakir [0000-0001-8647-1986]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/371712https://api.elsevier.com/content/abstract/scopus_id/85189030393reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de investigación Científica y Técnica y de Innovación 2021-2023/CEX2023-001263-SJournal of Molecular Liquidshttp://doi.org/10.1016/j.molliq.2024.124572Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3717122026-05-22T06:33:51Z
dc.title.none.fl_str_mv Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibition
Identification of promising Lysosomal α-Glucosidase (rhGAA) inhibitors: A mechanistic exploration through pharmacophore based virtual screening, molecular docking coupled with Molecular dynamic simulation
title Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibition
spellingShingle Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibition
Malik, Saima
Lysosomal α-glucosidase (GAA)
Molecular docking
Molecular dynamic simulation
PCA
title_short Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibition
title_full Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibition
title_fullStr Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibition
title_full_unstemmed Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibition
title_sort Unlocking potential diabetes therapeutics: Insights into alpha-glucosidase inhibition
dc.creator.none.fl_str_mv Malik, Saima
Lodhi, Muhammad Arif
Ayaz, Sultan
Ullah, Zakir
author Malik, Saima
author_facet Malik, Saima
Lodhi, Muhammad Arif
Ayaz, Sultan
Ullah, Zakir
author_role author
author2 Lodhi, Muhammad Arif
Ayaz, Sultan
Ullah, Zakir
author2_role author
author
author
dc.contributor.none.fl_str_mv Agencia Estatal de Investigación (España)
Ullah, Zakir [0000-0001-8647-1986]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Lysosomal α-glucosidase (GAA)
Molecular docking
Molecular dynamic simulation
PCA
topic Lysosomal α-glucosidase (GAA)
Molecular docking
Molecular dynamic simulation
PCA
description Diabetes mellitus (DM) stands as a significant global health challenge, ranking third among causes of mortality worldwide. Despite extensive endeavors, effective treatments for diabetes remain elusive. Alpha-glucosidase, a pivotal enzyme in glycoprotein metabolism regulation, emerges as a promising therapeutic target for mitigating postprandial hyperglycemia, a hallmark of diabetes. In this study, we employed advanced computational methodologies to identify inhibitors of lysosomal α-glucosidase. Leveraging pharmacophore-based virtual screening of a vast library of drug-like molecules, we unearthed 161 potential inhibitors capable of binding within the enzyme's active pocket. Subsequent molecular docking simulations yielded five lead molecules exhibiting robust binding affinities and favorable interaction profiles with critical catalytic residues. Further analysis through molecular dynamics simulations provided crucial insights into the stability and conformational dynamics of the inhibitor-enzyme complexes. Notably, certain residues emerged as pivotal for the retention of inhibitors within the active site. Our findings underscore the potential of LIG1-LIG5 as promising inhibitors against lysosomal α-glucosidase, presenting novel avenues for the development of effective diabetes therapeutics. This research enriches our understanding of the molecular underpinnings of diabetes treatment, facilitating targeted drug development strategies in the quest for improved patient outcomes.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/371712
https://api.elsevier.com/content/abstract/scopus_id/85189030393
url http://hdl.handle.net/10261/371712
https://api.elsevier.com/content/abstract/scopus_id/85189030393
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de investigación Científica y Técnica y de Innovación 2021-2023/CEX2023-001263-S
Journal of Molecular Liquids
http://doi.org/10.1016/j.molliq.2024.124572
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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