In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors.
Bioorg Med Chem Lett
; 28(6): 1116-1121, 2018 04 01.
Article
em En
| MEDLINE
| ID: mdl-29486968
ABSTRACT
The Wnt/ß-catenin signaling pathway is a key regulator of bone homeostasis. Sclerostin act as an extracellular inhibitor of canonical Wnt signaling through high-affinity binding to the Wnt co-receptor LRP5/6. Disruption of the interaction between LRP5/6 and sclerostin has been recognized as a therapeutic target for osteoporosis. We identified a quinoxaline moiety as a new small-molecule inhibitor of the LRP5/6-sclerostin interaction through pharmacophore-based virtual screening, docking simulations, and in vitro assays. Structure-activity relationship studies and binding mode hypotheses were used to optimize the scaffold and yield the compound BMD4503-2, which recovered the downregulated activity of the Wnt/ß-catenin signaling pathway by competitive binding to the LRP5/6-sclerostin complex. Overall, this study showed that the optimized structure-based drug design was a promising approach for the development of small-molecule inhibitors of the LRP5/6-sclerostin interaction. A novel scaffold offered considerable insights into the structural basis for binding to LRP5/6 and disruption of the sclerostin-mediated inhibition of Wnt signaling.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinoxalinas
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Proteínas Morfogenéticas Ósseas
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Descoberta de Drogas
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Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade
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Simulação de Acoplamento Molecular
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article