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    Por favor, use este identificador para citar o enlazar este ítem:https://uvadoc.uva.es/handle/10324/66545

    Título
    Evaluation of Cx43 gap junction inhibitors using a quantitative structure-activity relationship model
    Autor
    Matusevičiūtė, Ramona
    Ignatavičiūtė, Eglė
    Mickus, Rokas
    Bordel Velasco, SergioAutoridad UVA Orcid
    Skeberdis, Vytenis Arvydas
    Raškevičius, Vytautas
    Año del Documento
    2023
    Editorial
    MDPI
    Descripción
    Producción Científica
    Documento Fuente
    Biomedicines, 2023, Vol. 11, Nº. 7, 1972
    Resumo
    Gap junctions (GJs) made of connexin-43 (Cx43) are necessary for the conduction of electrical impulses in the heart. Modulation of Cx43 GJ activity may be beneficial in the treatment of cardiac arrhythmias and other dysfunctions. The search for novel GJ-modulating agents using molecular docking allows for the accurate prediction of binding affinities of ligands, which, unfortunately, often poorly correlate with their potencies. The objective of this study was to demonstrate that a Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using molecular docking, QSAR, and 3D-QSAR, we evaluated 16 known Cx43 GJ inhibitors, suggested the monocyclic monoterpene d-limonene as a putative Cx43 inhibitor, and tested it experimentally in HeLa cells expressing exogenous Cx43. The predicted concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds were compared with those determined experimentally (pIC50 and eIC50, respectively). The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR and 3D-QSAR models showed a good correlation with their eIC50ies (R = 0.88 and 0.90, respectively) in contrast to pIC50ies obtained from molecular docking (R = 0.78). However, molecular docking suggests that inhibitor potency may depend on their docking conformation on Cx43. Searching for new potent, selective, and specific inhibitors of GJ channels, we propose to perform the primary screening of new putative compounds using the QSAR model, followed by the validation of the most suitable candidates by patch-clamp techniques.
    Materias (normalizadas)
    Biomedicine, general
    Biomedicina
    Molecular biology
    Cardiology
    Cardiac surgery
    Corazón - Enfermedades
    Materias Unesco
    2302.21 Biología Molecular
    3205.01 Cardiología
    32 Ciencias Médicas
    Palabras Clave
    Gap junctions (Cell biology)
    Connexins
    Cx43
    Conductance
    Contundancia
    Inhibitors
    Inhibidores
    Docking
    Molecular docking
    Acoplamiento molecular
    ISSN
    2227-9059
    Revisión por pares
    SI
    DOI
    10.3390/biomedicines11071972
    Patrocinador
    Consejo de Investigación de Lituania - (grant S-MIP-23-105)
    Version del Editor
    https://www.mdpi.com/2227-9059/11/7/1972
    Propietario de los Derechos
    © 2023 The authors
    Idioma
    eng
    URI
    https://uvadoc.uva.es/handle/10324/66545
    Tipo de versión
    info:eu-repo/semantics/publishedVersion
    Derechos
    openAccess
    Aparece en las colecciones
    • IPS - Artículos de revista [157]
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    Evaluation-of-Cx43-Gap-Junction-Inhibitors.pdf
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