The Impact of polypharmacology on chemical biology

There is now ample evidence that drugs have biologically relevant interactions with more than one protein, a behavior that is commonly referred to as polypharmacology. This finding is starting to have a true impact on the drug discovery process, transforming it into a more holistic endeavor. In cont...

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Autor: Antolín Hernández, Albert
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2014
País:España
Recursos:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/329012
Acesso em linha:http://hdl.handle.net/10803/329012
Access Level:acceso abierto
Palavra-chave:Polypharmacology
Chemical biology
Protein target
Synthetic lethality
Molecular descriptor
Kinases
Biomarkers
Molecular docking
Polifarmacologia
Biologia química
Sonda química
Proteïna diana
Farmacologia de sistemes
Letalitat sintètica
Similatitat química
Descriptor molecular
Quinases
Biomarcador
Acoblament molecular
615
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv The Impact of polypharmacology on chemical biology
title The Impact of polypharmacology on chemical biology
spellingShingle The Impact of polypharmacology on chemical biology
Antolín Hernández, Albert
Polypharmacology
Chemical biology
Protein target
Synthetic lethality
Molecular descriptor
Kinases
Biomarkers
Molecular docking
Polifarmacologia
Biologia química
Sonda química
Proteïna diana
Farmacologia de sistemes
Letalitat sintètica
Similatitat química
Descriptor molecular
Quinases
Biomarcador
Acoblament molecular
615
title_short The Impact of polypharmacology on chemical biology
title_full The Impact of polypharmacology on chemical biology
title_fullStr The Impact of polypharmacology on chemical biology
title_full_unstemmed The Impact of polypharmacology on chemical biology
title_sort The Impact of polypharmacology on chemical biology
dc.creator.none.fl_str_mv Antolín Hernández, Albert
author Antolín Hernández, Albert
author_facet Antolín Hernández, Albert
author_role author
dc.contributor.none.fl_str_mv Mestres i López, Jordi
Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
dc.subject.none.fl_str_mv Polypharmacology
Chemical biology
Protein target
Synthetic lethality
Molecular descriptor
Kinases
Biomarkers
Molecular docking
Polifarmacologia
Biologia química
Sonda química
Proteïna diana
Farmacologia de sistemes
Letalitat sintètica
Similatitat química
Descriptor molecular
Quinases
Biomarcador
Acoblament molecular
615
topic Polypharmacology
Chemical biology
Protein target
Synthetic lethality
Molecular descriptor
Kinases
Biomarkers
Molecular docking
Polifarmacologia
Biologia química
Sonda química
Proteïna diana
Farmacologia de sistemes
Letalitat sintètica
Similatitat química
Descriptor molecular
Quinases
Biomarcador
Acoblament molecular
615
description There is now ample evidence that drugs have biologically relevant interactions with more than one protein, a behavior that is commonly referred to as polypharmacology. This finding is starting to have a true impact on the drug discovery process, transforming it into a more holistic endeavor. In contrast, chemical biology continues to be a reductionist discipline, still regarding chemical probes as highly selective small molecules that enable the modulation and study of one specific target. In an effort to bring a more comprehensive perspective to the practice of chemical biology, this Thesis aims at demonstrating that chemical probes, like drugs, tent to bind to more than one protein, a behavior that may have confounded many of the biological insights gathered using these tool compounds. Accordingly, in this Thesis we use the Poly(ADP-ribose) polymerase (PARP) enzyme superfamily to illustrate the consequences that chemical probe polypharmacology have for the practice of chemical biology and follow-on drug discovery. Next, we extend this analysis to a collection of chemical probes to demonstrate the ubiquity of polypharmacology and we provide guidelines to derisk the practice of chemical biology using potentially promiscuous tool compounds. Chemical biology cannot continue to overlook the existence of polypharmacology and the results presented in this Thesis urge it to become a more holistic discipline that looks at the use of tool compounds from a systems perspective.
publishDate 2014
dc.date.none.fl_str_mv 2014
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/329012
url http://hdl.handle.net/10803/329012
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-sa/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 283 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat Pompeu Fabra
publisher.none.fl_str_mv Universitat Pompeu Fabra
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling The Impact of polypharmacology on chemical biologyAntolín Hernández, AlbertPolypharmacologyChemical biologyProtein targetSynthetic lethalityMolecular descriptorKinasesBiomarkersMolecular dockingPolifarmacologiaBiologia químicaSonda químicaProteïna dianaFarmacologia de sistemesLetalitat sintèticaSimilatitat químicaDescriptor molecularQuinasesBiomarcadorAcoblament molecular615There is now ample evidence that drugs have biologically relevant interactions with more than one protein, a behavior that is commonly referred to as polypharmacology. This finding is starting to have a true impact on the drug discovery process, transforming it into a more holistic endeavor. In contrast, chemical biology continues to be a reductionist discipline, still regarding chemical probes as highly selective small molecules that enable the modulation and study of one specific target. In an effort to bring a more comprehensive perspective to the practice of chemical biology, this Thesis aims at demonstrating that chemical probes, like drugs, tent to bind to more than one protein, a behavior that may have confounded many of the biological insights gathered using these tool compounds. Accordingly, in this Thesis we use the Poly(ADP-ribose) polymerase (PARP) enzyme superfamily to illustrate the consequences that chemical probe polypharmacology have for the practice of chemical biology and follow-on drug discovery. Next, we extend this analysis to a collection of chemical probes to demonstrate the ubiquity of polypharmacology and we provide guidelines to derisk the practice of chemical biology using potentially promiscuous tool compounds. Chemical biology cannot continue to overlook the existence of polypharmacology and the results presented in this Thesis urge it to become a more holistic discipline that looks at the use of tool compounds from a systems perspective.Avui dia un gran nombre de proves demostren que els fàrmacs exerceixen interaccions biològicament rellevants amb més d’una proteïna, un comportament generalment anomenat polifarmacologia. Aquest descobriment està començant a influir en el procés de descobriment de fàrmacs, transformant-lo en una empresa més holística. Per contra, la biologia química continua essent una disciplina reduccionista que encara considera les sondes químiques com molècules molt selectives que permeten la modulació i l’estudi d’una diana específica. En un esforç per portar una visió més àmplia a la pràctica de la biologia química, aquesta Tesi té l’objectiu de demostrar que les sondes químiques, com els fàrmacs, tendeixen a unir-se amb més d’una diana, un comportament que podria haver confós moltes de les conclusions biològiques derivades del seu ús. En conseqüència, en aquesta Tesi utilitzem la superfamília de les proteïnes Poly(ADP-ribose) polymerasa (PARPs) per il•lustrar les conseqüències de la polifarmacologia de les sondes químiques en la pràctica de la biologia química i el conseqüent descobriment de fàrmacs. Seguidament, ampliem aquest anàlisi a una col•lecció de sondes químiques per demostrar la prevalença de la polifarmacologia i aportem recomanacions per a convertir l’ús de sondes químiques potencialment promiscues en biologia química en una pràctica menys arriscada. La biologia química no pot seguir obviant l’existència de la polifarmacologia i els resultats presentats en aquesta Tesi demostren que la biologia química ha d’esdevenir una disciplina més holística que consideri l’ús de sondes químiques des d’una perspectiva de sistemes.Programa de doctorat en BiomedicinaUniversitat Pompeu FabraMestres i López, JordiUniversitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut201520152014info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion283 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/329012TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-sa/3.0/es/http://creativecommons.org/licenses/by-nc-sa/3.0/es/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/3290122026-06-14T12:46:07Z
score 15,301603

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