Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase

Autores
Frey, Kathleen M.; Bertoletti, Nicole; Chan, Albert H.; Ippolito, Joseph A.; Bollini, Mariela; Spasov, Krasimir A.; Jorgensen, William L.; Anderson, Karen S.
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.
Fil: Frey, Kathleen M.. University of Yale; Estados Unidos
Fil: Bertoletti, Nicole. University of Yale; Estados Unidos
Fil: Chan, Albert H.. University of Yale; Estados Unidos
Fil: Ippolito, Joseph A.. University of Yale; Estados Unidos
Fil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina. University of Yale; Estados Unidos
Fil: Spasov, Krasimir A.. University of Yale; Estados Unidos
Fil: Jorgensen, William L.. University of Yale; Estados Unidos
Fil: Anderson, Karen S.. University of Yale; Estados Unidos
Materia
COMPUTATIONAL CHEMISTRY
DRUG DESIGN
HIV RT
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
STRUCTURAL STUDIES
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:11336/203785
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/203785
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse TranscriptaseFrey, Kathleen M.Bertoletti, NicoleChan, Albert H.Ippolito, Joseph A.Bollini, MarielaSpasov, Krasimir A.Jorgensen, William L.Anderson, Karen S.COMPUTATIONAL CHEMISTRYDRUG DESIGNHIV RTNON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORSSTRUCTURAL STUDIEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.Fil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Bertoletti, Nicole. University of Yale; Estados UnidosFil: Chan, Albert H.. University of Yale; Estados UnidosFil: Ippolito, Joseph A.. University of Yale; Estados UnidosFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados UnidosFrontiers Media2022-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/203785Frey, Kathleen M.; Bertoletti, Nicole; Chan, Albert H.; Ippolito, Joseph A.; Bollini, Mariela; et al.; Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase; Frontiers Media; Frontiers in Molecular Biosciences; 9; 2-2022; 1-132296-889XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fmolb.2022.805187/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fmolb.2022.805187info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:48:29Zoai:ri.conicet.gov.ar:11336/203785instacron: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 09:48:30.096CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
title Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
spellingShingle Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
Frey, Kathleen M.
COMPUTATIONAL CHEMISTRY
DRUG DESIGN
HIV RT
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
STRUCTURAL STUDIES
title_short Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
title_full Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
title_fullStr Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
title_full_unstemmed Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
title_sort Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
dc.creator.none.fl_str_mv Frey, Kathleen M.
Bertoletti, Nicole
Chan, Albert H.
Ippolito, Joseph A.
Bollini, Mariela
Spasov, Krasimir A.
Jorgensen, William L.
Anderson, Karen S.
author Frey, Kathleen M.
author_facet Frey, Kathleen M.
Bertoletti, Nicole
Chan, Albert H.
Ippolito, Joseph A.
Bollini, Mariela
Spasov, Krasimir A.
Jorgensen, William L.
Anderson, Karen S.
author_role author
author2 Bertoletti, Nicole
Chan, Albert H.
Ippolito, Joseph A.
Bollini, Mariela
Spasov, Krasimir A.
Jorgensen, William L.
Anderson, Karen S.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv COMPUTATIONAL CHEMISTRY
DRUG DESIGN
HIV RT
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
STRUCTURAL STUDIES
topic COMPUTATIONAL CHEMISTRY
DRUG DESIGN
HIV RT
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
STRUCTURAL STUDIES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.
Fil: Frey, Kathleen M.. University of Yale; Estados Unidos
Fil: Bertoletti, Nicole. University of Yale; Estados Unidos
Fil: Chan, Albert H.. University of Yale; Estados Unidos
Fil: Ippolito, Joseph A.. University of Yale; Estados Unidos
Fil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina. University of Yale; Estados Unidos
Fil: Spasov, Krasimir A.. University of Yale; Estados Unidos
Fil: Jorgensen, William L.. University of Yale; Estados Unidos
Fil: Anderson, Karen S.. University of Yale; Estados Unidos
description Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.
publishDate 2022
dc.date.none.fl_str_mv 2022-02
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/11336/203785
Frey, Kathleen M.; Bertoletti, Nicole; Chan, Albert H.; Ippolito, Joseph A.; Bollini, Mariela; et al.; Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase; Frontiers Media; Frontiers in Molecular Biosciences; 9; 2-2022; 1-13
2296-889X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/203785
identifier_str_mv Frey, Kathleen M.; Bertoletti, Nicole; Chan, Albert H.; Ippolito, Joseph A.; Bollini, Mariela; et al.; Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase; Frontiers Media; Frontiers in Molecular Biosciences; 9; 2-2022; 1-13
2296-889X
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://www.frontiersin.org/articles/10.3389/fmolb.2022.805187/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fmolb.2022.805187
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
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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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score 13.070432

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