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Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach.

Authors
  • Pessôa, Marco T C1
  • Alves, Silmara L G2
  • Taranto, Alex G3
  • Villar, José A F P2
  • Blanco, Gustavo4
  • Barbosa, Leandro A1
  • 1 a Laboratório de Bioquímica Celular , Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindú , Divinópolis , Brazil. , (Brazil)
  • 2 b Laboratório de Síntese Orgânica e Nanoestruturas , Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindú , Divinópolis , Brazil. , (Brazil)
  • 3 c Laboratório de Modelagem Molecular , Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindú , Divinópolis , Brazil. , (Brazil)
  • 4 d Department of Molecular and Integrative Physiology , Kansas University Medical Center , Kansas City , KS , USA.
Type
Published Article
Journal
Journal of Enzyme Inhibition and Medicinal Chemistry
Publisher
Informa UK (Taylor & Francis)
Publication Date
Dec 01, 2018
Volume
33
Issue
1
Pages
85–97
Identifiers
DOI: 10.1080/14756366.2017.1380637
PMID: 29115894
Source
Medline
Keywords
License
Unknown

Abstract

Digoxin and other cardiotonic steroids (CTS) exert their effect by inhibiting Na,K-ATPase (NKA) activity. CTS bind to the various NKA isoforms that are expressed in different cell types, which gives CTS their narrow therapeutic index. We have synthesised a series of digoxin derivatives (γ-Benzylidene digoxin derivatives) with substitutions in the lactone ring (including non-oxygen and ether groups), to obtain CTS with better NKA isoform specificity. Some of these derivatives show some NKA isoform selective effects, with BD-3, BD-8, and BD-13 increasing NKA α2 activity, BD-5 inhibiting NKA α1 and NKA α3, BD-10 reducing NKA α1, but stimulating NKA α2 and α3; and BD-14, BD-15, and BD-16 enhancing NKA α3 activity. A molecular-docking approach favoured NKA isoform specific interactions for the compounds that supported their observed activity. These results show that BD compounds are a new type of CTS with the capacity to target NKA activity in an isoform-specific manner.

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