The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach

The mechanism-based inactivation (MBI) of P450 by paroxetine was investigated by computational analysis. The drug-enzyme interactions were figured out through studying energy profiles of three competing mechanisms. The potency of paroxetine as P450's inhibitor was estimated based on the availab...

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Detalles Bibliográficos
Autores: Kamel, Emadeldin M., Lamsabhi, Al Mokhtar
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/698588
Acceso en línea:http://hdl.handle.net/10486/698588
https://dx.doi.org/10.1039/d0ob00529k
Access Level:acceso abierto
Palabra clave:Cytochrome P-450 Enzyme
Enzyme activation
Paroxetine
Computational methods
Cytochrome P450
Computational analysis
Computational approach
Irreversible inactivation
Enzymes
Química
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spelling The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approachKamel, Emadeldin M.Lamsabhi, Al MokhtarCytochrome P-450 EnzymeEnzyme activationParoxetineComputational methodsCytochrome P450ParoxetineComputational analysisComputational approachIrreversible inactivationEnzyme activationEnzymesQuímicaThe mechanism-based inactivation (MBI) of P450 by paroxetine was investigated by computational analysis. The drug-enzyme interactions were figured out through studying energy profiles of three competing mechanisms. The potency of paroxetine as P450's inhibitor was estimated based on the availability of two active sites for the MBI in the paroxetine structure. The inactivation by the amino site of paroxetine mainly proceedsviathe hydrogen atom transfer pathway because of the lower energy demand of its rate determining step. In addition, the low-spin state is the predominant route in the MBI at the methylenedioxo active site as a result of being rebound barrier-free mechanism. Our comparative investigation showed that inactivation at the secondary amine is thermodynamically more favorable because of the lower energy barrier of the dehydration mechanism of the hydroxylated paroxetine complex than its methylenedioxo counterpart. The results of docking analysis coincided with the outputs of DFT calculations since the docking pose with the lowest binding affinity is that for conformation with polar interaction between the amino group of paroxetine and the oxo moiety of P450's active site. Assessment of the molecular dynamics simulations trajectories revealed the favorable interaction of paroxetine with P450This work has DGI Projects No. CTQ2015-63997-C2Royal Society of ChemistryDepartamento de QuímicaFacultad de Ciencias20202020-04-06research articlehttp://purl.org/coar/resource_type/c_2df8fbb1AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/698588https://dx.doi.org/10.1039/d0ob00529kreponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6985882026-06-23T12:46:27Z
dc.title.none.fl_str_mv The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach
title The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach
spellingShingle The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach
Kamel, Emadeldin M.
Cytochrome P-450 Enzyme
Enzyme activation
Paroxetine
Computational methods
Cytochrome P450
Paroxetine
Computational analysis
Computational approach
Irreversible inactivation
Enzyme activation
Enzymes
Química
title_short The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach
title_full The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach
title_fullStr The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach
title_full_unstemmed The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach
title_sort The quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approach
dc.creator.none.fl_str_mv Kamel, Emadeldin M.
Lamsabhi, Al Mokhtar
author Kamel, Emadeldin M.
author_facet Kamel, Emadeldin M.
Lamsabhi, Al Mokhtar
author_role author
author2 Lamsabhi, Al Mokhtar
author2_role author
dc.contributor.none.fl_str_mv Departamento de Química
Facultad de Ciencias
dc.subject.none.fl_str_mv Cytochrome P-450 Enzyme
Enzyme activation
Paroxetine
Computational methods
Cytochrome P450
Paroxetine
Computational analysis
Computational approach
Irreversible inactivation
Enzyme activation
Enzymes
Química
topic Cytochrome P-450 Enzyme
Enzyme activation
Paroxetine
Computational methods
Cytochrome P450
Paroxetine
Computational analysis
Computational approach
Irreversible inactivation
Enzyme activation
Enzymes
Química
description The mechanism-based inactivation (MBI) of P450 by paroxetine was investigated by computational analysis. The drug-enzyme interactions were figured out through studying energy profiles of three competing mechanisms. The potency of paroxetine as P450's inhibitor was estimated based on the availability of two active sites for the MBI in the paroxetine structure. The inactivation by the amino site of paroxetine mainly proceedsviathe hydrogen atom transfer pathway because of the lower energy demand of its rate determining step. In addition, the low-spin state is the predominant route in the MBI at the methylenedioxo active site as a result of being rebound barrier-free mechanism. Our comparative investigation showed that inactivation at the secondary amine is thermodynamically more favorable because of the lower energy barrier of the dehydration mechanism of the hydroxylated paroxetine complex than its methylenedioxo counterpart. The results of docking analysis coincided with the outputs of DFT calculations since the docking pose with the lowest binding affinity is that for conformation with polar interaction between the amino group of paroxetine and the oxo moiety of P450's active site. Assessment of the molecular dynamics simulations trajectories revealed the favorable interaction of paroxetine with P450
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-04-06
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/698588
https://dx.doi.org/10.1039/d0ob00529k
url http://hdl.handle.net/10486/698588
https://dx.doi.org/10.1039/d0ob00529k
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Royal Society of Chemistry
publisher.none.fl_str_mv Royal Society of Chemistry
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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