Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces

Autores
Accordino, Sebastian Roberto; Morini, Marcela Ana; Sierra, Maria Belen; Rodriguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian; Fernandez, Ariel
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The discovery of small-molecule drugs aimed at disrupting protein-protein associations is expected to lead to promising therapeutic strategies. The small molecule binds to the target protein thus replacing its natural protein partner. Noteworthy, structural analysis of complexes between successful disruptive small molecules and their target proteins has suggested the possibility that such ligands might somehow mimic the binding behavior of the protein they replace. In these cases, the molecules show a spatial and "chemical" (i.e., hydrophobicity) similarity with the residues of the partner protein involved in the protein-protein complex interface. However, other disruptive small molecules do not seem to show such spatial and chemical correspondence with the replaced protein. In turn, recent progress in the understanding of protein-protein interactions and binding hot spots has revealed the main role of intermolecular wrapping interactions: three-body cooperative correlations in which nonpolar groups in the partner protein promote dehydration of a two-body electrostatic interaction of the other protein. Hence, in the present work, we study some successful complexes between already discovered small disruptive drug-like molecules and their target proteins already reported in the literature and we compare them with the complexes between such proteins and their natural protein partners. Our results show that the small molecules do in fact mimic to a great extent the wrapping behavior of the protein they replace. Thus, by revealing the replacement the small molecule performs of relevant wrapping interactions, we convey precise physical meaning to the mimicking concept, a knowledge that might be exploited in future drug-design endeavors. © 2012 Wiley Periodicals, Inc.
Fil: Accordino, Sebastian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Morini, Marcela Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Sierra, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Rodriguez Fris, Jorge Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Appignanesi, Gustavo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Fernandez, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática Alberto Calderón; Argentina
Materia
Binding
Design
Drug
Interface
Protein
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/64004
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfacesAccordino, Sebastian RobertoMorini, Marcela AnaSierra, Maria BelenRodriguez Fris, Jorge ArielAppignanesi, Gustavo AdrianFernandez, ArielBindingDesignDrugInterfaceProteinhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The discovery of small-molecule drugs aimed at disrupting protein-protein associations is expected to lead to promising therapeutic strategies. The small molecule binds to the target protein thus replacing its natural protein partner. Noteworthy, structural analysis of complexes between successful disruptive small molecules and their target proteins has suggested the possibility that such ligands might somehow mimic the binding behavior of the protein they replace. In these cases, the molecules show a spatial and "chemical" (i.e., hydrophobicity) similarity with the residues of the partner protein involved in the protein-protein complex interface. However, other disruptive small molecules do not seem to show such spatial and chemical correspondence with the replaced protein. In turn, recent progress in the understanding of protein-protein interactions and binding hot spots has revealed the main role of intermolecular wrapping interactions: three-body cooperative correlations in which nonpolar groups in the partner protein promote dehydration of a two-body electrostatic interaction of the other protein. Hence, in the present work, we study some successful complexes between already discovered small disruptive drug-like molecules and their target proteins already reported in the literature and we compare them with the complexes between such proteins and their natural protein partners. Our results show that the small molecules do in fact mimic to a great extent the wrapping behavior of the protein they replace. Thus, by revealing the replacement the small molecule performs of relevant wrapping interactions, we convey precise physical meaning to the mimicking concept, a knowledge that might be exploited in future drug-design endeavors. © 2012 Wiley Periodicals, Inc.Fil: Accordino, Sebastian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Morini, Marcela Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Sierra, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Rodriguez Fris, Jorge Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Appignanesi, Gustavo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Fernandez, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática Alberto Calderón; ArgentinaWiley-liss, Div John Wiley & Sons Inc2012-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/64004Accordino, Sebastian Roberto; Morini, Marcela Ana; Sierra, Maria Belen; Rodriguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian; et al.; Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces; Wiley-liss, Div John Wiley & Sons Inc; Proteins: Structure, Function And Genetics; 80; 7; 7-2012; 1755-17650887-3585CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1002/prot.24069info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1002/prot.24069info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:02:42Zoai:ri.conicet.gov.ar:11336/64004instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:02:43.282CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces
title Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces
spellingShingle Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces
Accordino, Sebastian Roberto
Binding
Design
Drug
Interface
Protein
title_short Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces
title_full Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces
title_fullStr Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces
title_full_unstemmed Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces
title_sort Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces
dc.creator.none.fl_str_mv Accordino, Sebastian Roberto
Morini, Marcela Ana
Sierra, Maria Belen
Rodriguez Fris, Jorge Ariel
Appignanesi, Gustavo Adrian
Fernandez, Ariel
author Accordino, Sebastian Roberto
author_facet Accordino, Sebastian Roberto
Morini, Marcela Ana
Sierra, Maria Belen
Rodriguez Fris, Jorge Ariel
Appignanesi, Gustavo Adrian
Fernandez, Ariel
author_role author
author2 Morini, Marcela Ana
Sierra, Maria Belen
Rodriguez Fris, Jorge Ariel
Appignanesi, Gustavo Adrian
Fernandez, Ariel
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Binding
Design
Drug
Interface
Protein
topic Binding
Design
Drug
Interface
Protein
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The discovery of small-molecule drugs aimed at disrupting protein-protein associations is expected to lead to promising therapeutic strategies. The small molecule binds to the target protein thus replacing its natural protein partner. Noteworthy, structural analysis of complexes between successful disruptive small molecules and their target proteins has suggested the possibility that such ligands might somehow mimic the binding behavior of the protein they replace. In these cases, the molecules show a spatial and "chemical" (i.e., hydrophobicity) similarity with the residues of the partner protein involved in the protein-protein complex interface. However, other disruptive small molecules do not seem to show such spatial and chemical correspondence with the replaced protein. In turn, recent progress in the understanding of protein-protein interactions and binding hot spots has revealed the main role of intermolecular wrapping interactions: three-body cooperative correlations in which nonpolar groups in the partner protein promote dehydration of a two-body electrostatic interaction of the other protein. Hence, in the present work, we study some successful complexes between already discovered small disruptive drug-like molecules and their target proteins already reported in the literature and we compare them with the complexes between such proteins and their natural protein partners. Our results show that the small molecules do in fact mimic to a great extent the wrapping behavior of the protein they replace. Thus, by revealing the replacement the small molecule performs of relevant wrapping interactions, we convey precise physical meaning to the mimicking concept, a knowledge that might be exploited in future drug-design endeavors. © 2012 Wiley Periodicals, Inc.
Fil: Accordino, Sebastian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Morini, Marcela Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Sierra, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Rodriguez Fris, Jorge Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Appignanesi, Gustavo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Fernandez, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática Alberto Calderón; Argentina
description The discovery of small-molecule drugs aimed at disrupting protein-protein associations is expected to lead to promising therapeutic strategies. The small molecule binds to the target protein thus replacing its natural protein partner. Noteworthy, structural analysis of complexes between successful disruptive small molecules and their target proteins has suggested the possibility that such ligands might somehow mimic the binding behavior of the protein they replace. In these cases, the molecules show a spatial and "chemical" (i.e., hydrophobicity) similarity with the residues of the partner protein involved in the protein-protein complex interface. However, other disruptive small molecules do not seem to show such spatial and chemical correspondence with the replaced protein. In turn, recent progress in the understanding of protein-protein interactions and binding hot spots has revealed the main role of intermolecular wrapping interactions: three-body cooperative correlations in which nonpolar groups in the partner protein promote dehydration of a two-body electrostatic interaction of the other protein. Hence, in the present work, we study some successful complexes between already discovered small disruptive drug-like molecules and their target proteins already reported in the literature and we compare them with the complexes between such proteins and their natural protein partners. Our results show that the small molecules do in fact mimic to a great extent the wrapping behavior of the protein they replace. Thus, by revealing the replacement the small molecule performs of relevant wrapping interactions, we convey precise physical meaning to the mimicking concept, a knowledge that might be exploited in future drug-design endeavors. © 2012 Wiley Periodicals, Inc.
publishDate 2012
dc.date.none.fl_str_mv 2012-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/64004
Accordino, Sebastian Roberto; Morini, Marcela Ana; Sierra, Maria Belen; Rodriguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian; et al.; Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces; Wiley-liss, Div John Wiley & Sons Inc; Proteins: Structure, Function And Genetics; 80; 7; 7-2012; 1755-1765
0887-3585
CONICET Digital
CONICET
url http://hdl.handle.net/11336/64004
identifier_str_mv Accordino, Sebastian Roberto; Morini, Marcela Ana; Sierra, Maria Belen; Rodriguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian; et al.; Wrapping mimicking in drug-like small molecules disruptive of protein-protein interfaces; Wiley-liss, Div John Wiley & Sons Inc; Proteins: Structure, Function And Genetics; 80; 7; 7-2012; 1755-1765
0887-3585
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1002/prot.24069
info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1002/prot.24069
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley-liss, Div John Wiley & Sons Inc
publisher.none.fl_str_mv Wiley-liss, Div John Wiley & Sons Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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