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Discovery of novel Flt3 inhibitory chemotypes through extensive ligand-based and new structure-based pharmacophore modelling methods
Ist Teil von
Journal of molecular graphics & modelling, 2019-05, Vol.88, p.128-151
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2019
Link zum Volltext
Quelle
Access via ScienceDirect (Elsevier)
Beschreibungen/Notizen
Flt3 is an oncogenic kinase involved in different types of leukemia. It is most prominently associated with acute myeloid leukemia (AML). Flt3-specific inhibitors have shown promising results in interfering with AML prompting us to model this interesting target. We implemented ligand-based, QSAR-guided, pharmacophore exploration combined with novel structure-based computational workflow based on docking-based comparative intermolecular contacts analysis (db-CICA) combined with homology modelling to explore the pharmacophoric features of 93 diverse cyclic Flt3 inhibitors. The resulting pharmacophore models were used as virtual search queries to scan the National Cancer Institute (NCI) database for novel Flt3 inhibitory leads. Ten hits of novel scaffolds were captured showing anti-Flt3 IC50 values ranging from 1.2 to 14.7 μM. Interestingly, six of them illustrated low micromolar and submicromolar potencies against the mutated active form of Flt3 (Flt3D835Y) and the related vascular endothelial growth factor receptor 2 (VEGFR2).
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•93 cyclic Flt3 inhibitors were collected from literature and used in modelling.•MLR- and kNN-QSAR used to achieve optimal ligand-based pharmacophores.•Homology modelling and db-CICA combined for optimal structure-based pharmacophores.•Pharmacophores validated by ROC and capture of novel micromolar leads.