A series of 6-arylquinazolin-4-amine analogs have been identified as inhibitors of Cdc2-like kinases (Clk1-4) and Dual Specificity Tyrosine-phosphorylation-regulated kinases (Dyrk1A and Dyrk1B). Among them, a chemical probe, or a potent and selective inhibitor of Cdc2-like kinase 4 (Clk4) was obtained. Understanding the protein-ligand interaction regarding this chemical probe will be aiding the future design of potent and high-selectivity inhibitors of Clk4. In this study, homology modeling and docking were applied to identify the binding characteristics of this probe to Clk4, in comparison with the binding modes of other 6-arylquinazolin-4-amine analogs. Ligand-based pharmacophore and 3D-QSAR analyses were performed in order to understand the structure-activity correlation of these analogs against Clk4 and Dyrk1A. The binding modes identified through docking were consistent with the structural properties featured by pharmacophore and 3D-QSAR models. The obtained 3D-QSAR models in combination with the binding modes between inhibitors and Clk4 will be helpful for future lead compound identification and optimization to design potent and selective Clk4 and Dyrk1A inhibitors.

Ligand- and structure-based characterization of protein-ligand interaction associated with Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A)

247th National Meeting (2014)

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