Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach.
J Enzyme Inhib Med Chem
; 33(1): 85-97, 2018 Dec.
Article
em En
| MEDLINE
| ID: mdl-29115894
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos de Benzilideno
/
ATPase Trocadora de Sódio-Potássio
/
Digoxina
/
Simulação de Acoplamento Molecular
Limite:
Animals
Idioma:
En
Revista:
J Enzyme Inhib Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Reino Unido