Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations

Autores
Felsztyna, Iván; Gastaldi, María Salomé; Villarreal, Marcos Ariel; Garcia, Daniel Asmed; Miguel, Virginia
Año de publicación
2020
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Insect nervous system is the main target for the most used insecticides, as is the case of GABAA receptor (GABAA-R) non-competitive antagonists (NCAs). In insects, the homopentamer formed by the Rdl subunit (Rdlhomo5) is the most representative type of GABAA-R. Rdlhomo5 presents several binding sites for NCAs. The NCA-IA site is located inside the channel pore and is targeted by polychlorocycloalkanes, cyclodienes and phenylpyrazoles. Also, a NCA-II site is located in the transmembrane domains interfaces and is targeted by fluralaner. Since there are no experimental 3D structures of any insect Rdlhomo5, in a previous work we performed homology modelling of Aedes aegypti Rdlhomo5 using templates in different pharmacological states. We aim to validate structural models suitable for performing virtual screening of new NCAs. We have now evaluated ten different Rdlhomo5 homology models by a retrospective virtual screening. A set of active ligands for the NCA-I site and a set of property-matched decoys were subjected to molecular docking. Virtual screening performance in these models was evaluated by the calculation of ROC curves and ligand enrichment factors. The model with the best performance was embedded in a POPC bilayer and subjected to ̴200 ns molecular dynamics simulations, both in the apo state and in complex with fipronil, a NCA-I site binder insecticide. The protein showed small RMSD values in both states, indicating the structure stability of the homology model. Also, the key interactions between fipronil and the Rdlhomo5 remained stable through the entire MD simulation time. We are currently evaluating the Rdlhomo5 models in regards to their performance for molecular docking in the NCA-II site. Our results show that several models based on different templates must be evaluated to obtain a trustworthy structure for the application of structure-based virtual screening in insect GABAA-R homology models.
Fil: Felsztyna, Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina
Fil: Gastaldi, María Salomé. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina
Fil: Villarreal, Marcos Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina
Fil: Garcia, Daniel Asmed. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina
Fil: Miguel, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina
Biofísica en tiempos de COVID-19 : Primeras Jornadas Virtuales SAB 2020
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
Materia
Molecular docking
Virtual screening
Homology modelling
Gabaergic insecticides
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:11336/228411
Acceder
id CONICETDig_e6586b1a3d745cb6f0ff989e2b0b4998
oai_identifier_str oai:ri.conicet.gov.ar:11336/228411
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulationsFelsztyna, IvánGastaldi, María SaloméVillarreal, Marcos ArielGarcia, Daniel AsmedMiguel, VirginiaMolecular dockingVirtual screeningHomology modellingGabaergic insecticideshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Insect nervous system is the main target for the most used insecticides, as is the case of GABAA receptor (GABAA-R) non-competitive antagonists (NCAs). In insects, the homopentamer formed by the Rdl subunit (Rdlhomo5) is the most representative type of GABAA-R. Rdlhomo5 presents several binding sites for NCAs. The NCA-IA site is located inside the channel pore and is targeted by polychlorocycloalkanes, cyclodienes and phenylpyrazoles. Also, a NCA-II site is located in the transmembrane domains interfaces and is targeted by fluralaner. Since there are no experimental 3D structures of any insect Rdlhomo5, in a previous work we performed homology modelling of Aedes aegypti Rdlhomo5 using templates in different pharmacological states. We aim to validate structural models suitable for performing virtual screening of new NCAs. We have now evaluated ten different Rdlhomo5 homology models by a retrospective virtual screening. A set of active ligands for the NCA-I site and a set of property-matched decoys were subjected to molecular docking. Virtual screening performance in these models was evaluated by the calculation of ROC curves and ligand enrichment factors. The model with the best performance was embedded in a POPC bilayer and subjected to ̴200 ns molecular dynamics simulations, both in the apo state and in complex with fipronil, a NCA-I site binder insecticide. The protein showed small RMSD values in both states, indicating the structure stability of the homology model. Also, the key interactions between fipronil and the Rdlhomo5 remained stable through the entire MD simulation time. We are currently evaluating the Rdlhomo5 models in regards to their performance for molecular docking in the NCA-II site. Our results show that several models based on different templates must be evaluated to obtain a trustworthy structure for the application of structure-based virtual screening in insect GABAA-R homology models.Fil: Felsztyna, Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Gastaldi, María Salomé. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Villarreal, Marcos Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Garcia, Daniel Asmed. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Miguel, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaBiofísica en tiempos de COVID-19 : Primeras Jornadas Virtuales SAB 2020Buenos AiresArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaDelfino, Jose MariaCelej, Maria SoledadAmbroggio, Ernesto Esteban2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectVirtualBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/228411Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations; Biofísica en tiempos de COVID-19 : Primeras Jornadas Virtuales SAB 2020; Buenos Aires; Argentina; 2020; 60-60978-987-27591-8-6CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/Nacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:35:00Zoai:ri.conicet.gov.ar:11336/228411instacron: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:34982025-09-29 09:35:00.989CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations
title Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations
spellingShingle Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations
Felsztyna, Iván
Molecular docking
Virtual screening
Homology modelling
Gabaergic insecticides
title_short Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations
title_full Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations
title_fullStr Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations
title_full_unstemmed Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations
title_sort Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations
dc.creator.none.fl_str_mv Felsztyna, Iván
Gastaldi, María Salomé
Villarreal, Marcos Ariel
Garcia, Daniel Asmed
Miguel, Virginia
author Felsztyna, Iván
author_facet Felsztyna, Iván
Gastaldi, María Salomé
Villarreal, Marcos Ariel
Garcia, Daniel Asmed
Miguel, Virginia
author_role author
author2 Gastaldi, María Salomé
Villarreal, Marcos Ariel
Garcia, Daniel Asmed
Miguel, Virginia
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Delfino, Jose Maria
Celej, Maria Soledad
Ambroggio, Ernesto Esteban
dc.subject.none.fl_str_mv Molecular docking
Virtual screening
Homology modelling
Gabaergic insecticides
topic Molecular docking
Virtual screening
Homology modelling
Gabaergic insecticides
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Insect nervous system is the main target for the most used insecticides, as is the case of GABAA receptor (GABAA-R) non-competitive antagonists (NCAs). In insects, the homopentamer formed by the Rdl subunit (Rdlhomo5) is the most representative type of GABAA-R. Rdlhomo5 presents several binding sites for NCAs. The NCA-IA site is located inside the channel pore and is targeted by polychlorocycloalkanes, cyclodienes and phenylpyrazoles. Also, a NCA-II site is located in the transmembrane domains interfaces and is targeted by fluralaner. Since there are no experimental 3D structures of any insect Rdlhomo5, in a previous work we performed homology modelling of Aedes aegypti Rdlhomo5 using templates in different pharmacological states. We aim to validate structural models suitable for performing virtual screening of new NCAs. We have now evaluated ten different Rdlhomo5 homology models by a retrospective virtual screening. A set of active ligands for the NCA-I site and a set of property-matched decoys were subjected to molecular docking. Virtual screening performance in these models was evaluated by the calculation of ROC curves and ligand enrichment factors. The model with the best performance was embedded in a POPC bilayer and subjected to ̴200 ns molecular dynamics simulations, both in the apo state and in complex with fipronil, a NCA-I site binder insecticide. The protein showed small RMSD values in both states, indicating the structure stability of the homology model. Also, the key interactions between fipronil and the Rdlhomo5 remained stable through the entire MD simulation time. We are currently evaluating the Rdlhomo5 models in regards to their performance for molecular docking in the NCA-II site. Our results show that several models based on different templates must be evaluated to obtain a trustworthy structure for the application of structure-based virtual screening in insect GABAA-R homology models.
Fil: Felsztyna, Iván. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina
Fil: Gastaldi, María Salomé. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina
Fil: Villarreal, Marcos Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina
Fil: Garcia, Daniel Asmed. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina
Fil: Miguel, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina
Biofísica en tiempos de COVID-19 : Primeras Jornadas Virtuales SAB 2020
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
description Insect nervous system is the main target for the most used insecticides, as is the case of GABAA receptor (GABAA-R) non-competitive antagonists (NCAs). In insects, the homopentamer formed by the Rdl subunit (Rdlhomo5) is the most representative type of GABAA-R. Rdlhomo5 presents several binding sites for NCAs. The NCA-IA site is located inside the channel pore and is targeted by polychlorocycloalkanes, cyclodienes and phenylpyrazoles. Also, a NCA-II site is located in the transmembrane domains interfaces and is targeted by fluralaner. Since there are no experimental 3D structures of any insect Rdlhomo5, in a previous work we performed homology modelling of Aedes aegypti Rdlhomo5 using templates in different pharmacological states. We aim to validate structural models suitable for performing virtual screening of new NCAs. We have now evaluated ten different Rdlhomo5 homology models by a retrospective virtual screening. A set of active ligands for the NCA-I site and a set of property-matched decoys were subjected to molecular docking. Virtual screening performance in these models was evaluated by the calculation of ROC curves and ligand enrichment factors. The model with the best performance was embedded in a POPC bilayer and subjected to ̴200 ns molecular dynamics simulations, both in the apo state and in complex with fipronil, a NCA-I site binder insecticide. The protein showed small RMSD values in both states, indicating the structure stability of the homology model. Also, the key interactions between fipronil and the Rdlhomo5 remained stable through the entire MD simulation time. We are currently evaluating the Rdlhomo5 models in regards to their performance for molecular docking in the NCA-II site. Our results show that several models based on different templates must be evaluated to obtain a trustworthy structure for the application of structure-based virtual screening in insect GABAA-R homology models.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Virtual
Book
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/228411
Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations; Biofísica en tiempos de COVID-19 : Primeras Jornadas Virtuales SAB 2020; Buenos Aires; Argentina; 2020; 60-60
978-987-27591-8-6
CONICET Digital
CONICET
url http://hdl.handle.net/11336/228411
identifier_str_mv Assessment of insect GABAA receptor homology models performance for virtual screening and their validation by molecular dynamics simulations; Biofísica en tiempos de COVID-19 : Primeras Jornadas Virtuales SAB 2020; Buenos Aires; Argentina; 2020; 60-60
978-987-27591-8-6
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/
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
dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Biofísica
publisher.none.fl_str_mv Sociedad Argentina de Biofísica
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
_version_ 1844613087940837376
score 13.070432

Publicaciones similares