A - Human Necessities – 61 – K
Patent
A - Human Necessities
61
K
A61K 31/27 (2006.01) A61K 31/00 (2006.01) A61K 31/165 (2006.01) A61K 31/166 (2006.01) A61K 31/194 (2006.01) A61K 31/216 (2006.01) A61K 31/519 (2006.01) A61K 45/00 (2006.01)
Patent
CA 2603642
The Wnt signaling pathways are involved in embryo development as well as in M tumorigenesis. Dishevelled (DvI) tra~'duces Wnt signals from the receptor Frizzled (Fz) to downstream components in canonical and non-canonical Wnt signaling pathways, and the DvI , PDZ domain plays an essential role in both pathways, and the DvI PDZ .domain binds directly to Fz receptors. In the present invention using NMR-assisted virtual ligand screening, several compounds were identified and were found to bind to the DvI PDZ domain. Molecular dynamics simulation was used to analyze the binding between the PDZ domain and these compounds in detail. These compounds provide a basis for rational design of high-affinity inhibitors of the PDZ domain, which can block Wnt signaling by interrupting the Fz-DvI interaction.
Les trajets de signalisation Wnt interviennent dans le développement de l'embryon et dans la tumorigenèse M. La protéine Dishevelled (DvI) assure la transduction des signaux à partir du récepteur Frizzled (Fz) vers les composantes aval dans les trajets de signalisation Wnt de type canonique et non canonique, et par ailleurs le domaine PDZ Dvl se lie directement avec les récepteurs Fz. En effectuant une analyse de ligand de type virtuel sous résonance magnétique nucléaire, on a identifié plusieurs composés se liant au domaine PDZ Dvl. Une simulation de dynamique moléculaire a été utilisée pour l'analyse détaillée de la liaison entre le domaine PDZ et ces composés. Les composés en question assurent une base de conception rationnelle d'inhibiteurs à haute affinité du domaine PDZ, pouvant bloquer la signalisation Wnt par interruption de l'interaction Fz-Dvl.
Shan Jufang
Wu Dianqing
Zheng Jie
Bereskin & Parr Llp/s.e.n.c.r.l.,s.r.l.
Enzo Biochem Inc.
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