Descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos

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Epilepsy is a disease characterized by the recurrent presence of seizures, with the neurobiological, cognitive, psychological, and social consequences that this implies. It affects more than 50 million people worldwide, which makes it the second most common neurological disease globally. The vast ma...

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Autor principal: Llanos, Manuel Augusto
Otros Autores: Gavernet, Luciana
Formato: Tesis Tesis de doctorado
Lenguaje:Español
Publicado: 2022
Materias:
Ciencias Exactas
Epilepsy
Drug Discovery
Ion channels
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/140503
https://doi.org/10.35537/10915/140503
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-140503
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Español
topic Ciencias Exactas
Epilepsy
Drug Discovery
Ion channels
spellingShingle Ciencias Exactas
Epilepsy
Drug Discovery
Ion channels
Llanos, Manuel Augusto
Descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos
topic_facet Ciencias Exactas
Epilepsy
Drug Discovery
Ion channels
description Epilepsy is a disease characterized by the recurrent presence of seizures, with the neurobiological, cognitive, psychological, and social consequences that this implies. It affects more than 50 million people worldwide, which makes it the second most common neurological disease globally. The vast majority of those affected live in low-income countries and as a consequence, nearly 75% of them do not receive appropriate treatment. Pharmacotherapy is the first-line treatment for this pathology. However, approximately 30% of patients do not respond to existing pharmacological therapies. This motivates the constant search for safer and better-tolerated anticonvulsant drugs (ACDs) that overcome the drug resistance problem. In this regard, this doctoral thesis aims to find multitarget compounds that act simultaneously on TRPV1 and NaV1.2 channels, with potential anticonvulsant activity in vivo, through a computer-aided drug repositioning strategy. For both molecular targets ligand- (QSAR) and structure-based (docking and molecular dynamics) predictive models were developed. The ensemble of models was applied in a virtual screening campaign over the DrugBank database, aiming to repurpose already approved drugs as ACDs, and three candidates were selected for experimental testing: Montelukast, Novobiocin, and Cinnarizine. All of them demonstrated a potent inhibitory activity on both targets, measured by the patch clamp technique on a heterologous expression system in HEK293 cells. Additionally, the candidates were tested in four animal models of seizures: MES, 6-hz, PTZ, and GASH:Sal. All drugs exhibited anticonvulsant activity in at least one of these models, and none of them showed signs of neurotoxicity in the Rotorod test. The combination of in silico methodologies, based on the structure of the ligands and the receptor, proved to be a useful approach for the identification of multitarget compounds in the context of a disease such as Epilepsy. Moreover, the joint modulation of TRPV1 and NaV1.2 channels emerge as a promising strategy for the development of novel ACDs.
author2 Gavernet, Luciana
author_facet Gavernet, Luciana
Llanos, Manuel Augusto
format Tesis
Tesis de doctorado
author Llanos, Manuel Augusto
author_sort Llanos, Manuel Augusto
title Descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos
title_short Descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos
title_full Descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos
title_fullStr Descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos
title_full_unstemmed Descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos
title_sort descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos
publishDate 2022
url http://sedici.unlp.edu.ar/handle/10915/140503
https://doi.org/10.35537/10915/140503
work_keys_str_mv AT llanosmanuelaugusto descubrimientodenuevosanticonvulsivosqueactuanmedianteinteraccionesconcanalesionicos
bdutipo_str Repositorios
_version_ 1764820459002527744

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