Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 228, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.114022
Keywords
Tropomyosin-receptor kinase A; Allosteric inhibitor; Virtual screening; Molecular dynamics simulation
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Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of tumors and chronic pain. This study discovered a novel TrkA allosteric inhibitor through structure-based virtual screening and conducted preliminary research on its properties.
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 mu M) 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. (C) 2021 Elsevier Masson SAS. All rights reserved.
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