Identification of new allosteric sites and modulators of AChE through computational and experimental tools

15 p.-10 fig.-5 tab.

Detalles Bibliográficos
Autores: Roca, Carlos, Requena-Triguero, Carlos, Sebastián-Pérez, Víctor, Malhotra, Sony, Radoux, Chris, Pérez, Concepción, Martínez Gil, Ana, Páez, Juan A., Blundell, Tom L., Campillo, Nuria E.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/166222
Acceso en línea:http://hdl.handle.net/10261/166222
Access Level:acceso abierto
Palabra clave:AChE
Alzheimer disease
Allosteric inhibitors
Allosteric sites
Molecular dynamics
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spelling Identification of new allosteric sites and modulators of AChE through computational and experimental toolsRoca, CarlosRequena-Triguero, CarlosSebastián-Pérez, VíctorMalhotra, SonyRadoux, ChrisPérez, ConcepciónMartínez Gil, AnaPáez, Juan A.Blundell, Tom L.Campillo, Nuria E.AChEAlzheimer diseaseAllosteric inhibitorsAllosteric sitesMolecular dynamics15 p.-10 fig.-5 tab.Allosteric sites on proteins are targeted for designing more selective inhibitors of enzyme activity and to discover new functions. Acetylcholinesterase (AChE), which is most widely known for the hydrolysis of the neurotransmitter acetylcholine, has a peripheral allosteric subsite responsible for amyloidosis in Alzheimer's disease through interaction with amyloid β-peptide. However, AChE plays other non-hydrolytic functions. Here, we identify and characterise using computational tools two new allosteric sites in AChE, which have allowed us to identify allosteric inhibitors by virtual screening guided by structure-based and fragment hotspot strategies. The identified compounds were also screened for in vitro inhibition of AChE and three were observed to be active. Further experimental (kinetic) and computational (molecular dynamics) studies have been performed to verify the allosteric activity. These new compounds may be valuable pharmacological tools in the study of non-cholinergic functions of AChE.We thank to Ministerio de Educación, Cultura y Deporte (Grant of V.S.P, FPU15/01465 and Grant of N.E.C., Programa “Salvador de Madariaga” PR2015–00476).Peer reviewedInforma HealthcareMinisterio de Educación, Cultura y Deporte (España)Sebastián-Pérez, Víctor [0000-0002-8248-4496]Malhotra, Sony [0000-0002-3165-9081]Radoux, Chris [0000-0002-7903-7310]Martínez, Ana [0000-0002-2707-8110]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201820182018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/166222reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1080/14756366.2018.1476502Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1662222026-05-22T06:33:51Z
dc.title.none.fl_str_mv Identification of new allosteric sites and modulators of AChE through computational and experimental tools
title Identification of new allosteric sites and modulators of AChE through computational and experimental tools
spellingShingle Identification of new allosteric sites and modulators of AChE through computational and experimental tools
Roca, Carlos
AChE
Alzheimer disease
Allosteric inhibitors
Allosteric sites
Molecular dynamics
title_short Identification of new allosteric sites and modulators of AChE through computational and experimental tools
title_full Identification of new allosteric sites and modulators of AChE through computational and experimental tools
title_fullStr Identification of new allosteric sites and modulators of AChE through computational and experimental tools
title_full_unstemmed Identification of new allosteric sites and modulators of AChE through computational and experimental tools
title_sort Identification of new allosteric sites and modulators of AChE through computational and experimental tools
dc.creator.none.fl_str_mv Roca, Carlos
Requena-Triguero, Carlos
Sebastián-Pérez, Víctor
Malhotra, Sony
Radoux, Chris
Pérez, Concepción
Martínez Gil, Ana
Páez, Juan A.
Blundell, Tom L.
Campillo, Nuria E.
author Roca, Carlos
author_facet Roca, Carlos
Requena-Triguero, Carlos
Sebastián-Pérez, Víctor
Malhotra, Sony
Radoux, Chris
Pérez, Concepción
Martínez Gil, Ana
Páez, Juan A.
Blundell, Tom L.
Campillo, Nuria E.
author_role author
author2 Requena-Triguero, Carlos
Sebastián-Pérez, Víctor
Malhotra, Sony
Radoux, Chris
Pérez, Concepción
Martínez Gil, Ana
Páez, Juan A.
Blundell, Tom L.
Campillo, Nuria E.
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Educación, Cultura y Deporte (España)
Sebastián-Pérez, Víctor [0000-0002-8248-4496]
Malhotra, Sony [0000-0002-3165-9081]
Radoux, Chris [0000-0002-7903-7310]
Martínez, Ana [0000-0002-2707-8110]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv AChE
Alzheimer disease
Allosteric inhibitors
Allosteric sites
Molecular dynamics
topic AChE
Alzheimer disease
Allosteric inhibitors
Allosteric sites
Molecular dynamics
description 15 p.-10 fig.-5 tab.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/166222
url http://hdl.handle.net/10261/166222
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1080/14756366.2018.1476502
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Informa Healthcare
publisher.none.fl_str_mv Informa Healthcare
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
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869413236710834176
score 15,812429

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