Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs

Autores
Felsztyna, Iván; Villarreal, Marcos Ariel; Garcia, Daniel Asmed; Miguel, Virginia
Año de publicación
2021
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Pentameric ligand-gated ion channels (pLGICs) constitute a large family of transmembrane receptors. This family includes the γ-aminobutyric acid (GABA) receptors. The RDL homopentamer is the main GABA receptor in the insect nervous system. It presents structural differences with vertebrate GABAA receptors that result in a particular pharmacological profile. Therefore, the RDL receptor (RDL-R) is one of the most relevant targets for insecticides. Due to the difficulties related to pLGICs crystallization, many studies have used homology modeling to obtain the structure of these proteins and to perform computational studies about their ligands binding. However, the impact that the template conformational state could have on the model virtual screening (VS) performance has not been studied in detail. The aim of this work is to obtain RDL-R homology models in different conformational states and to evaluate their performance in a retrospective VS of channel-blocker insecticides. Fifteen RDL-R models were obtained, based on different pLGICs templates, whose structures represent three conformational states: closed, open and desensitized. With these models, molecular docking assays were performed with a set of active ligands and decoys. To evaluate the VS performance, the area under the ROC curve and the BEDROC score were calculated for each of the models. In addition, molecular dynamics simulations (MDS) were performed for the best models among each of the conformational states. The initial structures were obtained from the docking poses of the insecticide fipronil. VS performance parameters showed variations according to the conformational state of the templates. The correlations of these parameters with different variables were evaluated to analyze which were the determinant factors for a correct identification of active ligands. Structural properties of the channel pore, such as the solvent-accessible area and volume and the pore diameter at some specific residues could explain the differences in VS performance. The best results were obtained for a model based on a closed template. MDS confirmed that the expected interactions between the binding site residues and fipronil were present only in the closed model. These results show that different templates should be explored to obtain accurate RDL homology models, particularly focusing on the template conformational state. The model that presented the best performance parameters could be used in a prospective VS.
Fil: Felsztyna, Iván. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; Argentina. 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. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Teórica y Computacional; 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. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; 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. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Teórica y Computacional; Argentina
XLIX Reunión Anual de la Sociedad Argentina de Biofísica
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
Materia
GABAA receptor
Insecticide
Docking
Virtual screening
Fipronil
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:11336/189317
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/189317
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICsFelsztyna, IvánVillarreal, Marcos ArielGarcia, Daniel AsmedMiguel, VirginiaGABAA receptorInsecticideDockingVirtual screeningFipronilhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Pentameric ligand-gated ion channels (pLGICs) constitute a large family of transmembrane receptors. This family includes the γ-aminobutyric acid (GABA) receptors. The RDL homopentamer is the main GABA receptor in the insect nervous system. It presents structural differences with vertebrate GABAA receptors that result in a particular pharmacological profile. Therefore, the RDL receptor (RDL-R) is one of the most relevant targets for insecticides. Due to the difficulties related to pLGICs crystallization, many studies have used homology modeling to obtain the structure of these proteins and to perform computational studies about their ligands binding. However, the impact that the template conformational state could have on the model virtual screening (VS) performance has not been studied in detail. The aim of this work is to obtain RDL-R homology models in different conformational states and to evaluate their performance in a retrospective VS of channel-blocker insecticides. Fifteen RDL-R models were obtained, based on different pLGICs templates, whose structures represent three conformational states: closed, open and desensitized. With these models, molecular docking assays were performed with a set of active ligands and decoys. To evaluate the VS performance, the area under the ROC curve and the BEDROC score were calculated for each of the models. In addition, molecular dynamics simulations (MDS) were performed for the best models among each of the conformational states. The initial structures were obtained from the docking poses of the insecticide fipronil. VS performance parameters showed variations according to the conformational state of the templates. The correlations of these parameters with different variables were evaluated to analyze which were the determinant factors for a correct identification of active ligands. Structural properties of the channel pore, such as the solvent-accessible area and volume and the pore diameter at some specific residues could explain the differences in VS performance. The best results were obtained for a model based on a closed template. MDS confirmed that the expected interactions between the binding site residues and fipronil were present only in the closed model. These results show that different templates should be explored to obtain accurate RDL homology models, particularly focusing on the template conformational state. The model that presented the best performance parameters could be used in a prospective VS.Fil: Felsztyna, Iván. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; Argentina. 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; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Teórica y Computacional; 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; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; 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; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Teórica y Computacional; ArgentinaXLIX Reunión Anual de la Sociedad Argentina de BiofísicaBuenos AiresArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaDelfino, Jose MariaCelej, Maria SoledadMangialavori, Irene CeciliaAcierno, Juan Pablo2021info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/189317Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2021; 86-86978-987-27591-9-3CONICET 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 Técnicas2025-10-15T14:25:44Zoai:ri.conicet.gov.ar:11336/189317instacron: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:34982025-10-15 14:25:44.737CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs
title Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs
spellingShingle Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs
Felsztyna, Iván
GABAA receptor
Insecticide
Docking
Virtual screening
Fipronil
title_short Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs
title_full Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs
title_fullStr Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs
title_full_unstemmed Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs
title_sort Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs
dc.creator.none.fl_str_mv Felsztyna, Iván
Villarreal, Marcos Ariel
Garcia, Daniel Asmed
Miguel, Virginia
author Felsztyna, Iván
author_facet Felsztyna, Iván
Villarreal, Marcos Ariel
Garcia, Daniel Asmed
Miguel, Virginia
author_role author
author2 Villarreal, Marcos Ariel
Garcia, Daniel Asmed
Miguel, Virginia
author2_role author
author
author
dc.contributor.none.fl_str_mv Delfino, Jose Maria
Celej, Maria Soledad
Mangialavori, Irene Cecilia
Acierno, Juan Pablo
dc.subject.none.fl_str_mv GABAA receptor
Insecticide
Docking
Virtual screening
Fipronil
topic GABAA receptor
Insecticide
Docking
Virtual screening
Fipronil
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Pentameric ligand-gated ion channels (pLGICs) constitute a large family of transmembrane receptors. This family includes the γ-aminobutyric acid (GABA) receptors. The RDL homopentamer is the main GABA receptor in the insect nervous system. It presents structural differences with vertebrate GABAA receptors that result in a particular pharmacological profile. Therefore, the RDL receptor (RDL-R) is one of the most relevant targets for insecticides. Due to the difficulties related to pLGICs crystallization, many studies have used homology modeling to obtain the structure of these proteins and to perform computational studies about their ligands binding. However, the impact that the template conformational state could have on the model virtual screening (VS) performance has not been studied in detail. The aim of this work is to obtain RDL-R homology models in different conformational states and to evaluate their performance in a retrospective VS of channel-blocker insecticides. Fifteen RDL-R models were obtained, based on different pLGICs templates, whose structures represent three conformational states: closed, open and desensitized. With these models, molecular docking assays were performed with a set of active ligands and decoys. To evaluate the VS performance, the area under the ROC curve and the BEDROC score were calculated for each of the models. In addition, molecular dynamics simulations (MDS) were performed for the best models among each of the conformational states. The initial structures were obtained from the docking poses of the insecticide fipronil. VS performance parameters showed variations according to the conformational state of the templates. The correlations of these parameters with different variables were evaluated to analyze which were the determinant factors for a correct identification of active ligands. Structural properties of the channel pore, such as the solvent-accessible area and volume and the pore diameter at some specific residues could explain the differences in VS performance. The best results were obtained for a model based on a closed template. MDS confirmed that the expected interactions between the binding site residues and fipronil were present only in the closed model. These results show that different templates should be explored to obtain accurate RDL homology models, particularly focusing on the template conformational state. The model that presented the best performance parameters could be used in a prospective VS.
Fil: Felsztyna, Iván. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; Argentina. 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. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Teórica y Computacional; 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. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; 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. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Teórica y Computacional; Argentina
XLIX Reunión Anual de la Sociedad Argentina de Biofísica
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
description Pentameric ligand-gated ion channels (pLGICs) constitute a large family of transmembrane receptors. This family includes the γ-aminobutyric acid (GABA) receptors. The RDL homopentamer is the main GABA receptor in the insect nervous system. It presents structural differences with vertebrate GABAA receptors that result in a particular pharmacological profile. Therefore, the RDL receptor (RDL-R) is one of the most relevant targets for insecticides. Due to the difficulties related to pLGICs crystallization, many studies have used homology modeling to obtain the structure of these proteins and to perform computational studies about their ligands binding. However, the impact that the template conformational state could have on the model virtual screening (VS) performance has not been studied in detail. The aim of this work is to obtain RDL-R homology models in different conformational states and to evaluate their performance in a retrospective VS of channel-blocker insecticides. Fifteen RDL-R models were obtained, based on different pLGICs templates, whose structures represent three conformational states: closed, open and desensitized. With these models, molecular docking assays were performed with a set of active ligands and decoys. To evaluate the VS performance, the area under the ROC curve and the BEDROC score were calculated for each of the models. In addition, molecular dynamics simulations (MDS) were performed for the best models among each of the conformational states. The initial structures were obtained from the docking poses of the insecticide fipronil. VS performance parameters showed variations according to the conformational state of the templates. The correlations of these parameters with different variables were evaluated to analyze which were the determinant factors for a correct identification of active ligands. Structural properties of the channel pore, such as the solvent-accessible area and volume and the pore diameter at some specific residues could explain the differences in VS performance. The best results were obtained for a model based on a closed template. MDS confirmed that the expected interactions between the binding site residues and fipronil were present only in the closed model. These results show that different templates should be explored to obtain accurate RDL homology models, particularly focusing on the template conformational state. The model that presented the best performance parameters could be used in a prospective VS.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
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/11336/189317
Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2021; 86-86
978-987-27591-9-3
CONICET Digital
CONICET
url http://hdl.handle.net/11336/189317
identifier_str_mv Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2021; 86-86
978-987-27591-9-3
CONICET Digital
CONICET
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language eng
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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/
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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
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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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