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dc.contributor.author | Andreu Ros, María Inmaculada![]() |
es_ES |
dc.contributor.author | Lence, Emilio![]() |
es_ES |
dc.contributor.author | González-Bello, Concepción![]() |
es_ES |
dc.contributor.author | Mayorga, Cristobalina![]() |
es_ES |
dc.contributor.author | Cuquerella Alabort, Maria Consuelo![]() |
es_ES |
dc.contributor.author | Vayá Pérez, Ignacio![]() |
es_ES |
dc.contributor.author | Miranda Alonso, Miguel Ángel![]() |
es_ES |
dc.date.accessioned | 2021-06-15T03:31:22Z | |
dc.date.available | 2021-06-15T03:31:22Z | |
dc.date.issued | 2020-10-30 | es_ES |
dc.identifier.uri | http://hdl.handle.net/10251/167977 | |
dc.description.abstract | [EN] Lapatinib (LAP) is an anticancer drug generally used to treat breast and lung cancer. It exhibits hypersensitivity reactions in addition to dermatological adverse effects and photosensitivity. Moreover, LAP binds to serum proteins and is readily biotransformed in humans, giving rise to several metabolites, such as N- and O-dealkylated products (N-LAP and O-LAP, respectively). In this context, the aim of the present work is to obtain key information on drug@protein complexation, the first step involved in a number of hypersensitivity reactions, by a combination of fluorescence, femtosecond transient absorption spectroscopy and molecular dynamics (MD) simulations. Following this approach, the behavior of LAP and its metabolites has been investigated in the presence of serum proteins, such as albumins and alpha(1)-acid glycoproteins (SAs and AGs, respectively) from human and bovine origin. Fluorescence results pointed to a higher affinity of LAP and its metabolites to human proteins; the highest one was found for LAP@HSA. This is associated to the coplanar orientation adopted by the furan and quinazoline rings of LAP, which favors emission from long-lived (up to the ns time-scale) locally-excited (LE) states, disfavoring population of intramolecular charge transfer (ICT) states. Moreover, the highly constrained environment provided by subdomain IB of HSA resulted in a frozen conformation of the ligand, contributing to fluorescence enhancement. Computational studies were clearly in line with the experimental observations, providing valuable insight into the nature of the binding sites and the conformational arrangement of the ligands inside the protein cavities. Besides, a good correlation was found between the calculated binding energies for each ligand@protein complex and the relative affinities observed in competition experiments. | es_ES |
dc.description.sponsorship | Financial support from the Spanish Government (RYC-201517737, CTQ2017-89416-R, SAF2016-75638-R ISCIII grants RETICS ARADyAL (RD16/0006/0004 and RD16/0006/0001), PI16/01877 and CPII16/00052), Conselleria d'Educacio Cultura i Esport (PROMETEO/2017/075), the Xunta de Galicia [ED431B 2018/04 and Centro singular de investigacion de Galicia accreditation 2019-2022 (ED431G 2019/03)] and the European Regional Development Fund is gratefully acknowledged. | es_ES |
dc.language | Inglés | es_ES |
dc.publisher | Frontiers Media SA | es_ES |
dc.relation.ispartof | Frontiers in Pharmacology | es_ES |
dc.rights | Reconocimiento (by) | es_ES |
dc.subject | Femtosecond transient absorption | es_ES |
dc.subject | Fluorescence | es_ES |
dc.subject | Hypersensitivity reactions | es_ES |
dc.subject | Lapatinib | es_ES |
dc.subject | Metabolites | es_ES |
dc.subject | Molecular dynamics simulations | es_ES |
dc.subject | Protein binding | es_ES |
dc.subject.classification | QUIMICA ORGANICA | es_ES |
dc.title | Protein binding of lapatinib and its N- and O-dealkylated metabolites interrogated by fluorescence, ultrafast spectroscopy and molecular dynamics simulations | es_ES |
dc.type | Artículo | es_ES |
dc.identifier.doi | 10.3389/fphar.2020.576495 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/MINECO//SAF2016-75638-R/ES/DESARROLLO DE NUEVOS FARMACOS PARA EL TRATAMIENTO DE LAS INFECCIONES BACTERIANAS MULTIRESISTENTES: APROXIMACIONES QUE INCIDEN SOBRE VIABILIDAD, RESISTENCIA Y VIRULENCIA/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/Xunta de Galicia//ED431B 2018%2F04/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/MINECO//CPII16%2F00052/ES/CPII16%2F00052/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/MINECO//RYC-2015-17737/ES/RYC-2015-17737/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/CTQ2017-89416-R/ES/FUNCIONALIZACION DE NANOPARTICULAS DE ORO CON MARCADORES BIOLOGICOS Y SENSIBILIZADORES DE OXIGENO SINGLETE PARA SU USO EN BIOMEDICINA/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/Xunta de Galicia//ED431G 2019%2F03/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/MINECO//RD16%2F0006%2F0004/ES/Asma, Reacciones Adversas y Alérgicas (ARADYAL)/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/MINECO//RD16%2F0006%2F0001/ES/Asma, Reacciones Adversas y Alérgicas (ARADYAL)/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/MINECO//PI16%2F01877/ES/Estrategia integrada de fotodiagnóstico combinando evaluación clínica, ensayos biológicos y estudios mecanísticos/ | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/GVA//PROMETEO%2F2017%2F075/ES/Reacciones fotoquímicas de biomoléculas/ | es_ES |
dc.rights.accessRights | Abierto | es_ES |
dc.contributor.affiliation | Universitat Politècnica de València. Departamento de Química - Departament de Química | es_ES |
dc.contributor.affiliation | Universitat Politècnica de València. Instituto Universitario Mixto de Tecnología Química - Institut Universitari Mixt de Tecnologia Química | es_ES |
dc.description.bibliographicCitation | Andreu Ros, MI.; Lence, E.; González-Bello, C.; Mayorga, C.; Cuquerella Alabort, MC.; Vayá Pérez, I.; Miranda Alonso, MÁ. (2020). Protein binding of lapatinib and its N- and O-dealkylated metabolites interrogated by fluorescence, ultrafast spectroscopy and molecular dynamics simulations. Frontiers in Pharmacology. 11:1-11. https://doi.org/10.3389/fphar.2020.576495 | es_ES |
dc.description.accrualMethod | S | es_ES |
dc.relation.publisherversion | https://doi.org/10.3389/fphar.2020.576495 | es_ES |
dc.description.upvformatpinicio | 1 | es_ES |
dc.description.upvformatpfin | 11 | es_ES |
dc.type.version | info:eu-repo/semantics/publishedVersion | es_ES |
dc.description.volume | 11 | es_ES |
dc.identifier.eissn | 1663-9812 | es_ES |
dc.identifier.pmid | 33192518 | es_ES |
dc.identifier.pmcid | PMC7662899 | es_ES |
dc.relation.pasarela | S\422607 | es_ES |
dc.contributor.funder | Xunta de Galicia | es_ES |
dc.contributor.funder | Generalitat Valenciana | es_ES |
dc.contributor.funder | Agencia Estatal de Investigación | es_ES |
dc.contributor.funder | European Regional Development Fund | es_ES |
dc.contributor.funder | Ministerio de Economía y Competitividad | es_ES |
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