Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor

Autores
Felsztyna, Iván; Villarreal, Marcos Ariel; Garcia, Daniel Asmed; Miguel, Virginia
Año de publicación
2022
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Pentameric ligand-gated ion channels (pLGICs) constitute a large family of transmembrane proteins that includes the γ-aminobutyric acid receptors (GABA-R). The RDL receptor (RDL-R) is the main GABA-R in the insect nervous system and it 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 their structures and to perform docking-based virtual screening (VS). However, the impact that the template conformational state could exert on the model VS performance has not been studied in detail. The aim of this work was 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 in three conformational states: closed, open and desensitized. With these models, molecular docking assays were performed with active ligands and decoys. To evaluate the VS performance, the area under the ROC curve and the BEDROC score were calculated. Besides, molecular dynamics simulations (MDS) were performed for the best models among each of the conformational states in complex with the insecticide fipronil. VS performance parameters showed variations according to the conformational state of the templates. These parameters were correlated with different variables to analyze which were the determinant factors for a good VS performance. The solvent-accessible area and volume and the pore diameter explained 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 and fipronil were present only in that model. 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 is suitable for a prospective VS.
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: 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
7th Annual Biophysical Society of Canada/IUPAB Ion Channel Biophysics Meeting
Ottawa
Canadá
University of Ottawa
Materia
PLGICs
GABA RECEPTORS
HOMOLOGY MODELING
VIRTUAL SCREENING
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:11336/200750
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/200750
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptorFelsztyna, IvánVillarreal, Marcos ArielGarcia, Daniel AsmedMiguel, VirginiaPLGICsGABA RECEPTORSHOMOLOGY MODELINGVIRTUAL SCREENINGhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Pentameric ligand-gated ion channels (pLGICs) constitute a large family of transmembrane proteins that includes the γ-aminobutyric acid receptors (GABA-R). The RDL receptor (RDL-R) is the main GABA-R in the insect nervous system and it 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 their structures and to perform docking-based virtual screening (VS). However, the impact that the template conformational state could exert on the model VS performance has not been studied in detail. The aim of this work was 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 in three conformational states: closed, open and desensitized. With these models, molecular docking assays were performed with active ligands and decoys. To evaluate the VS performance, the area under the ROC curve and the BEDROC score were calculated. Besides, molecular dynamics simulations (MDS) were performed for the best models among each of the conformational states in complex with the insecticide fipronil. VS performance parameters showed variations according to the conformational state of the templates. These parameters were correlated with different variables to analyze which were the determinant factors for a good VS performance. The solvent-accessible area and volume and the pore diameter explained 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 and fipronil were present only in that model. 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 is suitable for a prospective VS.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: 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; Argentina7th Annual Biophysical Society of Canada/IUPAB Ion Channel Biophysics MeetingOttawaCanadáUniversity of OttawaUniversity of Ottawa2022info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/200750Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor; 7th Annual Biophysical Society of Canada/IUPAB Ion Channel Biophysics Meeting; Ottawa; Canadá; 2022CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://event.fourwaves.com/jointbsc2022iupab/abstracts/819a3657-6f6c-4898-9d22-c7410126416ainfo:eu-repo/semantics/altIdentifier/url/https://event.fourwaves.com/jointbsc2022iupab/abstracts?page=4Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:23:25Zoai:ri.conicet.gov.ar:11336/200750instacron: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 10:23:25.985CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor
title Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor
spellingShingle Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor
Felsztyna, Iván
PLGICs
GABA RECEPTORS
HOMOLOGY MODELING
VIRTUAL SCREENING
title_short Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor
title_full Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor
title_fullStr Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor
title_full_unstemmed Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor
title_sort Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor
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.subject.none.fl_str_mv PLGICs
GABA RECEPTORS
HOMOLOGY MODELING
VIRTUAL SCREENING
topic PLGICs
GABA RECEPTORS
HOMOLOGY MODELING
VIRTUAL SCREENING
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 proteins that includes the γ-aminobutyric acid receptors (GABA-R). The RDL receptor (RDL-R) is the main GABA-R in the insect nervous system and it 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 their structures and to perform docking-based virtual screening (VS). However, the impact that the template conformational state could exert on the model VS performance has not been studied in detail. The aim of this work was 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 in three conformational states: closed, open and desensitized. With these models, molecular docking assays were performed with active ligands and decoys. To evaluate the VS performance, the area under the ROC curve and the BEDROC score were calculated. Besides, molecular dynamics simulations (MDS) were performed for the best models among each of the conformational states in complex with the insecticide fipronil. VS performance parameters showed variations according to the conformational state of the templates. These parameters were correlated with different variables to analyze which were the determinant factors for a good VS performance. The solvent-accessible area and volume and the pore diameter explained 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 and fipronil were present only in that model. 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 is suitable for a prospective VS.
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: 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
7th Annual Biophysical Society of Canada/IUPAB Ion Channel Biophysics Meeting
Ottawa
Canadá
University of Ottawa
description Pentameric ligand-gated ion channels (pLGICs) constitute a large family of transmembrane proteins that includes the γ-aminobutyric acid receptors (GABA-R). The RDL receptor (RDL-R) is the main GABA-R in the insect nervous system and it 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 their structures and to perform docking-based virtual screening (VS). However, the impact that the template conformational state could exert on the model VS performance has not been studied in detail. The aim of this work was 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 in three conformational states: closed, open and desensitized. With these models, molecular docking assays were performed with active ligands and decoys. To evaluate the VS performance, the area under the ROC curve and the BEDROC score were calculated. Besides, molecular dynamics simulations (MDS) were performed for the best models among each of the conformational states in complex with the insecticide fipronil. VS performance parameters showed variations according to the conformational state of the templates. These parameters were correlated with different variables to analyze which were the determinant factors for a good VS performance. The solvent-accessible area and volume and the pore diameter explained 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 and fipronil were present only in that model. 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 is suitable for a prospective VS.
publishDate 2022
dc.date.none.fl_str_mv 2022
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/11336/200750
Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor; 7th Annual Biophysical Society of Canada/IUPAB Ion Channel Biophysics Meeting; Ottawa; Canadá; 2022
CONICET Digital
CONICET
url http://hdl.handle.net/11336/200750
identifier_str_mv Impact of the template conformational state on pLGICs homology models applicability for virtual screening: A case study on the insect GABA receptor; 7th Annual Biophysical Society of Canada/IUPAB Ion Channel Biophysics Meeting; Ottawa; Canadá; 2022
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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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 Internacional
dc.publisher.none.fl_str_mv University of Ottawa
publisher.none.fl_str_mv University of Ottawa
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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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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