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

Journal of Enzyme Inhibition and Medicinal Chemistry

Gustavo Blanco¹  Leandro A. Barbosa²  Marco T. C. Pessôa²  Alex G. Taranto³  Silmara L. G. Alves⁴  José A. F. P. Villar⁴ 

[1] Department of Molecular and Integrative Physiology, Kansas University Medical Center, Kansas City, KS, US;Laboratório de Bioquímica Celular, Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindú, Divinópolis, Brazil;Laboratório de Modelagem Molecular, Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindú, Divinópolis, Brazil;Laboratório de Síntese Orgânica e Nanoestruturas, Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindú, Divinópolis, Brazil;

关键词: Cardiotonic steroids;    digoxin;    Na,K-ATPase isoforms;    molecular docking;   

DOI  :  10.1080/14756366.2017.1380637

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY