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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/189317
Ver los metadatos del registro completo
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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 |
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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 |
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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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Sociedad Argentina de Biofísica |
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Sociedad Argentina de Biofísica |
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