Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles

Computer-aided strategies are useful for reducing the costs and increasing the success-rate in drug discovery. Among these strategies, methods based on pharmacophores (an ensemble of electronic and steric features representing the target active site) are efficient to implement over large compound li...

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Detalhes bibliográficos
Autores: Lans, Isaias, Palacio Rodríguez, Karen, Cavasotto, Claudio Norberto, Cossio, Pilar
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:Argentina
Recursos:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/184518
Acesso em linha:http://hdl.handle.net/11336/184518
Access Level:acceso abierto
Palavra-chave:AFFINITY MAP
DRUG DISCOVERY
DYNAMICS
ENRICHMENT
LIGAND-FREE PHARMACOPHORE
VIRTUAL SCREENING
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
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spelling Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensemblesLans, IsaiasPalacio Rodríguez, KarenCavasotto, Claudio NorbertoCossio, PilarAFFINITY MAPDRUG DISCOVERYDYNAMICSENRICHMENTLIGAND-FREE PHARMACOPHOREVIRTUAL SCREENINGhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Computer-aided strategies are useful for reducing the costs and increasing the success-rate in drug discovery. Among these strategies, methods based on pharmacophores (an ensemble of electronic and steric features representing the target active site) are efficient to implement over large compound libraries. However, traditional pharmacophore-based methods require knowledge of active compounds or ligand–receptor structures, and only few ones account for target flexibility. Here, we developed a pharmacophore-based virtual screening protocol, Flexi-pharma, that overcomes these limitations. The protocol uses molecular dynamics (MD) simulations to explore receptor flexibility, and performs a pharmacophore-based virtual screening over a set of MD conformations without requiring prior knowledge about known ligands or ligand–receptor structures for building the pharmacophores. The results from the different receptor conformations are combined using a “voting” approach, where a vote is given to each molecule that matches at least one pharmacophore from each MD conformation. Contrarily to other approaches that reduce the pharmacophore ensemble to some representative models and score according to the matching models or molecule conformers, the Flexi-pharma approach takes directly into account the receptor flexibility by scoring in regards to the receptor conformations. We tested the method over twenty systems, finding an enrichment of the dataset for 19 of them. Flexi-pharma is computationally efficient allowing for the screening of thousands of compounds in minutes on a single CPU core. Moreover, the ranking of molecules by vote is a general strategy that can be applied with any pharmacophore-filtering program.Fil: Lans, Isaias. Universidad de Antioquia; ColombiaFil: Palacio Rodríguez, Karen. Universidad de Antioquia; ColombiaFil: Cavasotto, Claudio Norberto. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Cossio, Pilar. Max Planck Institute Of Biophysics; Alemania. Universidad de Antioquia; ColombiaSpringer2020-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/184518Lans, Isaias; Palacio Rodríguez, Karen; Cavasotto, Claudio Norberto; Cossio, Pilar; Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles; Springer; Journal of Computer-Aided Molecular Design; 34; 10; 7-2020; 1063-10770920-654XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007/s10822-020-00329-7info:eu-repo/semantics/altIdentifier/doi/10.1007/s10822-020-00329-7info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2024-05-08T13:33:58Zoai:ri.conicet.gov.ar:11336/184518instacron: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:34982024-05-08 13:33:59.137CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles
title Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles
spellingShingle Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles
Lans, Isaias
AFFINITY MAP
DRUG DISCOVERY
DYNAMICS
ENRICHMENT
LIGAND-FREE PHARMACOPHORE
VIRTUAL SCREENING
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
title_short Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles
title_full Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles
title_fullStr Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles
title_full_unstemmed Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles
title_sort Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles
dc.creator.none.fl_str_mv Lans, Isaias
Palacio Rodríguez, Karen
Cavasotto, Claudio Norberto
Cossio, Pilar
author Lans, Isaias
author_facet Lans, Isaias
Palacio Rodríguez, Karen
Cavasotto, Claudio Norberto
Cossio, Pilar
author_role author
author2 Palacio Rodríguez, Karen
Cavasotto, Claudio Norberto
Cossio, Pilar
author2_role author
author
author
dc.subject.none.fl_str_mv AFFINITY MAP
DRUG DISCOVERY
DYNAMICS
ENRICHMENT
LIGAND-FREE PHARMACOPHORE
VIRTUAL SCREENING
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
topic AFFINITY MAP
DRUG DISCOVERY
DYNAMICS
ENRICHMENT
LIGAND-FREE PHARMACOPHORE
VIRTUAL SCREENING
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
description Computer-aided strategies are useful for reducing the costs and increasing the success-rate in drug discovery. Among these strategies, methods based on pharmacophores (an ensemble of electronic and steric features representing the target active site) are efficient to implement over large compound libraries. However, traditional pharmacophore-based methods require knowledge of active compounds or ligand–receptor structures, and only few ones account for target flexibility. Here, we developed a pharmacophore-based virtual screening protocol, Flexi-pharma, that overcomes these limitations. The protocol uses molecular dynamics (MD) simulations to explore receptor flexibility, and performs a pharmacophore-based virtual screening over a set of MD conformations without requiring prior knowledge about known ligands or ligand–receptor structures for building the pharmacophores. The results from the different receptor conformations are combined using a “voting” approach, where a vote is given to each molecule that matches at least one pharmacophore from each MD conformation. Contrarily to other approaches that reduce the pharmacophore ensemble to some representative models and score according to the matching models or molecule conformers, the Flexi-pharma approach takes directly into account the receptor flexibility by scoring in regards to the receptor conformations. We tested the method over twenty systems, finding an enrichment of the dataset for 19 of them. Flexi-pharma is computationally efficient allowing for the screening of thousands of compounds in minutes on a single CPU core. Moreover, the ranking of molecules by vote is a general strategy that can be applied with any pharmacophore-filtering program.
publishDate 2020
dc.date.none.fl_str_mv 2020-07
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/11336/184518
Lans, Isaias; Palacio Rodríguez, Karen; Cavasotto, Claudio Norberto; Cossio, Pilar; Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles; Springer; Journal of Computer-Aided Molecular Design; 34; 10; 7-2020; 1063-1077
0920-654X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/184518
identifier_str_mv Lans, Isaias; Palacio Rodríguez, Karen; Cavasotto, Claudio Norberto; Cossio, Pilar; Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles; Springer; Journal of Computer-Aided Molecular Design; 34; 10; 7-2020; 1063-1077
0920-654X
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://link.springer.com/article/10.1007/s10822-020-00329-7
info:eu-repo/semantics/altIdentifier/doi/10.1007/s10822-020-00329-7
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
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 15,812429

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