Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents

Autores
Vietri, Agustin; Obiol, Diego Javier; Munafó, Juan Pablo; Costabel, Marcelo Daniel; Antollini, Silvia Susana
Año de publicación
2025
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
The main objective of this study was to identify an analog capable of acting on multiple relevant targets in Alzheimer’s disease (AD), thereby achieving an integral treatment of this condition through a single molecule. To this end, we designed twenty-nine caffeine analogs aimed at enhancing cholinergic activity, modulating apoptosis and immunity, and promoting neuroprotection. We thoroughly analyzed the pharmacokinetic and molecular properties of each analog, performing molecular docking studies on fourteen targets (using virtual screening, blind docking, or both, depending on the target) to evaluate binding affinity. Pharmacokinetic parameters were predicted using Deep-PK and SwissADME, and molecular docking was performed using the Docthor online software. Validation of results were achieved by incorporating decoy molecules, positive controls, and ROC curve analyses. Among the candidates, analog T-49-I emerged as the most promising due to its strong multi-target affinity and favorable pharmacokinetic profile. However, we also identified other analogs that, despite less favorable pharmacokinetics, displayed selective affinity for specific targets or target groups relevant to particular therapeutic goals. Furthermore, we uncovered common molecular features that could guide the rational design of future analogs. This study provides qualitative structure– activity relationship insights that are valuable for developing multitarget molecules capable of simultaneously modulating various therapeutic targets in AD.
Fil: Vietri, Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Obiol, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Munafó, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Antollini, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
LIII Reunión Anual de la Sociedad Argentina de Biofísica
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
Materia
ALZHEIMER'S DISEASE
CAFFEINE ANALOGUES
MULTI-TARGET MOLECULES
PHARMACOKINETICS PROFILE
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:11336/279788
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s AgentsVietri, AgustinObiol, Diego JavierMunafó, Juan PabloCostabel, Marcelo DanielAntollini, Silvia SusanaALZHEIMER'S DISEASECAFFEINE ANALOGUESMULTI-TARGET MOLECULESPHARMACOKINETICS PROFILEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The main objective of this study was to identify an analog capable of acting on multiple relevant targets in Alzheimer’s disease (AD), thereby achieving an integral treatment of this condition through a single molecule. To this end, we designed twenty-nine caffeine analogs aimed at enhancing cholinergic activity, modulating apoptosis and immunity, and promoting neuroprotection. We thoroughly analyzed the pharmacokinetic and molecular properties of each analog, performing molecular docking studies on fourteen targets (using virtual screening, blind docking, or both, depending on the target) to evaluate binding affinity. Pharmacokinetic parameters were predicted using Deep-PK and SwissADME, and molecular docking was performed using the Docthor online software. Validation of results were achieved by incorporating decoy molecules, positive controls, and ROC curve analyses. Among the candidates, analog T-49-I emerged as the most promising due to its strong multi-target affinity and favorable pharmacokinetic profile. However, we also identified other analogs that, despite less favorable pharmacokinetics, displayed selective affinity for specific targets or target groups relevant to particular therapeutic goals. Furthermore, we uncovered common molecular features that could guide the rational design of future analogs. This study provides qualitative structure– activity relationship insights that are valuable for developing multitarget molecules capable of simultaneously modulating various therapeutic targets in AD.Fil: Vietri, Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Obiol, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Munafó, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Antollini, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaLIII Reunión Anual de la Sociedad Argentina de BiofísicaBuenos AiresArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaVazquez, Diego SebastianDi Lella, Santiago2025info: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/11336/279788Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents; LIII Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2025; 105-105978-987-48938-3-3CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/congreso-2025/#resumenesNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-06T12:09:39Zoai:ri.conicet.gov.ar:11336/279788instacron: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:34982026-02-06 12:09:39.666CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents
title Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents
spellingShingle Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents
Vietri, Agustin
ALZHEIMER'S DISEASE
CAFFEINE ANALOGUES
MULTI-TARGET MOLECULES
PHARMACOKINETICS PROFILE
title_short Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents
title_full Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents
title_fullStr Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents
title_full_unstemmed Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents
title_sort Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents
dc.creator.none.fl_str_mv Vietri, Agustin
Obiol, Diego Javier
Munafó, Juan Pablo
Costabel, Marcelo Daniel
Antollini, Silvia Susana
author Vietri, Agustin
author_facet Vietri, Agustin
Obiol, Diego Javier
Munafó, Juan Pablo
Costabel, Marcelo Daniel
Antollini, Silvia Susana
author_role author
author2 Obiol, Diego Javier
Munafó, Juan Pablo
Costabel, Marcelo Daniel
Antollini, Silvia Susana
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Vazquez, Diego Sebastian
Di Lella, Santiago
dc.subject.none.fl_str_mv ALZHEIMER'S DISEASE
CAFFEINE ANALOGUES
MULTI-TARGET MOLECULES
PHARMACOKINETICS PROFILE
topic ALZHEIMER'S DISEASE
CAFFEINE ANALOGUES
MULTI-TARGET MOLECULES
PHARMACOKINETICS PROFILE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The main objective of this study was to identify an analog capable of acting on multiple relevant targets in Alzheimer’s disease (AD), thereby achieving an integral treatment of this condition through a single molecule. To this end, we designed twenty-nine caffeine analogs aimed at enhancing cholinergic activity, modulating apoptosis and immunity, and promoting neuroprotection. We thoroughly analyzed the pharmacokinetic and molecular properties of each analog, performing molecular docking studies on fourteen targets (using virtual screening, blind docking, or both, depending on the target) to evaluate binding affinity. Pharmacokinetic parameters were predicted using Deep-PK and SwissADME, and molecular docking was performed using the Docthor online software. Validation of results were achieved by incorporating decoy molecules, positive controls, and ROC curve analyses. Among the candidates, analog T-49-I emerged as the most promising due to its strong multi-target affinity and favorable pharmacokinetic profile. However, we also identified other analogs that, despite less favorable pharmacokinetics, displayed selective affinity for specific targets or target groups relevant to particular therapeutic goals. Furthermore, we uncovered common molecular features that could guide the rational design of future analogs. This study provides qualitative structure– activity relationship insights that are valuable for developing multitarget molecules capable of simultaneously modulating various therapeutic targets in AD.
Fil: Vietri, Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Obiol, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Munafó, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Antollini, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
LIII Reunión Anual de la Sociedad Argentina de Biofísica
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
description The main objective of this study was to identify an analog capable of acting on multiple relevant targets in Alzheimer’s disease (AD), thereby achieving an integral treatment of this condition through a single molecule. To this end, we designed twenty-nine caffeine analogs aimed at enhancing cholinergic activity, modulating apoptosis and immunity, and promoting neuroprotection. We thoroughly analyzed the pharmacokinetic and molecular properties of each analog, performing molecular docking studies on fourteen targets (using virtual screening, blind docking, or both, depending on the target) to evaluate binding affinity. Pharmacokinetic parameters were predicted using Deep-PK and SwissADME, and molecular docking was performed using the Docthor online software. Validation of results were achieved by incorporating decoy molecules, positive controls, and ROC curve analyses. Among the candidates, analog T-49-I emerged as the most promising due to its strong multi-target affinity and favorable pharmacokinetic profile. However, we also identified other analogs that, despite less favorable pharmacokinetics, displayed selective affinity for specific targets or target groups relevant to particular therapeutic goals. Furthermore, we uncovered common molecular features that could guide the rational design of future analogs. This study provides qualitative structure– activity relationship insights that are valuable for developing multitarget molecules capable of simultaneously modulating various therapeutic targets in AD.
publishDate 2025
dc.date.none.fl_str_mv 2025
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/11336/279788
Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents; LIII Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2025; 105-105
978-987-48938-3-3
CONICET Digital
CONICET
url http://hdl.handle.net/11336/279788
identifier_str_mv Biophysical Evaluation of Caffeine Analogues as Multi-Targeted AntiAlzheimer’s Agents; LIII Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2025; 105-105
978-987-48938-3-3
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://biofisica.org.ar/congreso-2025/#resumenes
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
application/pdf
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
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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