Discovery of novel TrkA allosteric inhibitors: Structure-based virtual screening, biological evaluation and preliminary SAR studies.
Eur J Med Chem
; 228: 114022, 2022 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-34871843
ABSTRACT
Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of numerous tumor types and chronic pain. However, most of the reported TrkA inhibitors are ATP competitive pan-Trks inhibitors that lack subtype selectivity. A selective TrkA inhibitor may provide valuable therapeutic benefits. Here, we described the discovery of novel TrkA allosteric inhibitors by structure-based virtual screening. A promising hit (D5261, TrkA cell IC50 = 3.32 µM) was selected for further studies. The binding free energy between TrkA and D5261 was calculated. In addition, the preliminary structure-activity relationship (SAR) studies with D5261 were investigated. The results suggest that D5261 can be used as a starting point for development of TrkA allosteric inhibitors.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptor trkA
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Inibidores de Proteínas Quinases
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Descoberta de Drogas
Tipo de estudo:
Diagnostic_studies
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Screening_studies
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2022
Tipo de documento:
Article