Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes

25 p.-5 fig.-1 tab. + 6 fig. supl.+ 1 tab. supl.

Detalhes bibliográficos
Autores: La Sala, Giuseppina, Olieric, Natacha, Sharma, Ashwani, Viti, Federica, Balaguer, Francisco de Asís, Huang, Lan, Tonra, James R., Lloyd, George Kenneth, Decherchi, Sergio, Díaz, José Fernando, Steinmetz, Michel O., Cavalli, Andrea
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/198993
Acesso em linha:http://hdl.handle.net/10261/198993
Access Level:acceso abierto
Palavra-chave:Cancer
X-ray crystallography
Computational chemistry
Drug discovery
Drug development
Microtubules
Tubulin
Microtubule-targeting agents
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spelling Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin IsotypesLa Sala, GiuseppinaOlieric, NatachaSharma, AshwaniViti, FedericaBalaguer, Francisco de AsísHuang, LanTonra, James R.Lloyd, George KennethDecherchi, SergioDíaz, José FernandoSteinmetz, Michel O.Cavalli, AndreaCancerX-ray crystallographyComputational chemistryDrug discoveryDrug developmentMicrotubulesTubulinMicrotubule-targeting agents25 p.-5 fig.-1 tab. + 6 fig. supl.+ 1 tab. supl.αβ-Tubulin is a validated target for anticancer drug discovery, and molecules binding to this protein are used to treat several types of tumors. Here, we report on a combined X-ray crystallography and molecular dynamics approach to study drug binding within the colchicine site of αβ-tubulin, focusing on plinabulin, an agent currently in phase 3 clinical testing for the treatment of cancer and chemotherapy-induced neutropenia. We found that plinabulin is more persistently bound to the colchicine site of βII- compared to βIII-tubulin, allowing for a prediction of isotype-expression-dependent drug sensitivity. Additionally, computational residence time and exit paths from the βII-tubulin were compared between plinabulin and two other compounds, colchicine and combretastatin-A4. The former displayed the highest residence time, followed by plinabulin and then distantly by combretastatin-A4. Our combined experimental and computational protocol could help to investigate anti-tubulin drugs, improving our understanding of their mechanism of action, residence time, and tubulin isotype selectivity.This work was financially supported by BeyondSpring Pharmaceuticals Inc. (to M.O.S. and A.C.) and by grants from the Ministerio de Ciencia Innovacion y Universidades (BFU2016-75319-R; to J.F.D.), from the Swiss National Science Foundation (31003A_166608, to M.O.S.) and from the Regione Lombardia (Accordo per la Ricerca e l’Innovazione).Peer reviewedElsevierBeyondSpring PharmaceuticalsMinisterio de Ciencia, Innovación y Universidades (España)Swiss National Science FoundationRegione LombardiaLa Sala, Giuseppina [0000-0001-6565-197X]Olieric, Natacha [0000-0002-6273-390X]Viti, Federica [0000-0002-9651-8896]Decherchi, Sergio [0000-0001-8371-2270]Díaz, José Fernando [0000-0003-2743-3319]Steinmetz, Michel O. [0000-0001-6157-3687]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/198993reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-75319-Rhttps://doi.org/10.1016/j.chempr.2019.08.022Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1989932026-05-22T06:33:51Z
dc.title.none.fl_str_mv Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes
title Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes
spellingShingle Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes
La Sala, Giuseppina
Cancer
X-ray crystallography
Computational chemistry
Drug discovery
Drug development
Microtubules
Tubulin
Microtubule-targeting agents
title_short Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes
title_full Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes
title_fullStr Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes
title_full_unstemmed Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes
title_sort Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes
dc.creator.none.fl_str_mv La Sala, Giuseppina
Olieric, Natacha
Sharma, Ashwani
Viti, Federica
Balaguer, Francisco de Asís
Huang, Lan
Tonra, James R.
Lloyd, George Kenneth
Decherchi, Sergio
Díaz, José Fernando
Steinmetz, Michel O.
Cavalli, Andrea
author La Sala, Giuseppina
author_facet La Sala, Giuseppina
Olieric, Natacha
Sharma, Ashwani
Viti, Federica
Balaguer, Francisco de Asís
Huang, Lan
Tonra, James R.
Lloyd, George Kenneth
Decherchi, Sergio
Díaz, José Fernando
Steinmetz, Michel O.
Cavalli, Andrea
author_role author
author2 Olieric, Natacha
Sharma, Ashwani
Viti, Federica
Balaguer, Francisco de Asís
Huang, Lan
Tonra, James R.
Lloyd, George Kenneth
Decherchi, Sergio
Díaz, José Fernando
Steinmetz, Michel O.
Cavalli, Andrea
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv BeyondSpring Pharmaceuticals
Ministerio de Ciencia, Innovación y Universidades (España)
Swiss National Science Foundation
Regione Lombardia
La Sala, Giuseppina [0000-0001-6565-197X]
Olieric, Natacha [0000-0002-6273-390X]
Viti, Federica [0000-0002-9651-8896]
Decherchi, Sergio [0000-0001-8371-2270]
Díaz, José Fernando [0000-0003-2743-3319]
Steinmetz, Michel O. [0000-0001-6157-3687]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cancer
X-ray crystallography
Computational chemistry
Drug discovery
Drug development
Microtubules
Tubulin
Microtubule-targeting agents
topic Cancer
X-ray crystallography
Computational chemistry
Drug discovery
Drug development
Microtubules
Tubulin
Microtubule-targeting agents
description 25 p.-5 fig.-1 tab. + 6 fig. supl.+ 1 tab. supl.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
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/10261/198993
url http://hdl.handle.net/10261/198993
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/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-75319-R
https://doi.org/10.1016/j.chempr.2019.08.022
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
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869421776301195265
score 15,812455

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