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Pharmacophore and 3D-QSAR characterization of 6-arylquinazolin-4-amines as Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) inhibitors.

ABSTRACT: Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) are protein kinases that are promising targets for treatment of diseases caused by abnormal gene splicing. 6-Arylquinazolin-4-amines have been recently identified as potent Clk4 and Dyrk1A inhibitors. In order to understand the structure-activity correlation of these analogs, we have applied ligand-based pharmacophore and 3D-QSAR modeling combined with structure-based homology modeling and docking. The high R(2) and Q(2) (0.88 and 0.79 for Clk4, 0.85 and 0.82 for Dyrk1A, respectively) based on validation with training and test set compounds suggested that the generated 3D-QSAR models are reliable in predicting novel ligand activities against Clk4 and Dyrk1A. The binding mode identified through docking ligands to the ATP binding domain of Clk4 was consistent with the structural properties and energy field contour maps characterized by pharmacophore and 3D-QSAR models and gave valuable insights into the structure-activity profile of 6-arylquinazolin-4-amine analogs. The obtained 3D-QSAR and pharmacophore models in combination with the binding mode between inhibitor and residues of Clk4 will be helpful for future lead compound identification and optimization to design potent and selective Clk4 and Dyrk1A inhibitors.

SUBMITTER: Pan Y

PROVIDER: S-EPMC3633254 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Pharmacophore and 3D-QSAR characterization of 6-arylquinazolin-4-amines as Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) inhibitors.

Pan Yongmei Y Wang Yanli Y Bryant Stephen H SH

Journal of chemical information and modeling 20130404 4

Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) are protein kinases that are promising targets for treatment of diseases caused by abnormal gene splicing. 6-Arylquinazolin-4-amines have been recently identified as potent Clk4 and Dyrk1A inhibitors. In order to understand the structure-activity correlation of these analogs, we have applied ligand-based pharmacophore and 3D-QSAR modeling combined with structure-based homology modeling and dockin ...[more]

PMID: 23496085

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Project description:Using a three-pronged MS-based proteomic approach, we assessed the mode-of-action of four clinically-relevant tyrosine kinase inhibitors in an epithelial cancer cell line. Here we defined the: (I) semi-quantitative tyrosine kinome; (II) drug interactome; and (III) drug-induced effects on the tyrosine signalome. We first examined the entire proteome and kinome profile expressed in the A431 cell line, and determined the relative abundance of all possible protein targets of the tyrosine kinase inhibitors. We therefore utilized a ‘shot-gun’ approach that involved a multidimensional separation-based proteomic strategy. To ensure maximal protein identification, we reduced sample complexity by strong cation exchange (SCX) chromatography, and analyzed all fractions by LC-MS/MS. To determine the direct targets of the four selected TKIs, we subjected the proteins extracted from the A431 cancer cell line to drug-coupled affinity matrices. By comparing the pull-down results from a lysate with a second identical lysate to which 20 uM of the inhibitor had been added to block binding to the beads, we were able to identify selective binding interactors using LC-MS/MS. This differential affinity pull-downs approach allowed us to also quantitatively evaluate the binding affinity of the tyrosine kinases to each of the drugs. To evaluate the global tyrosine phosphorylation dynamics that occurs in A431 cells upon treatment with each of the four inhibitors, phosphotyrosine peptides were enriched and identified by quantitative mass spectrometry. For this purpose, we treated the cells with each inhibitor for 2 h at appropriate concentrations adopted from reported studies. Cells were lysed, and the proteins digested with the proteases Lys-C and trypsin. To allow quantitation of the phosphorylated peptides originating from the three different peptide pools (control/imatinib/dasatinib or control/bosutinib/nilotinib), we used stable isotope dimethyl labeling. Subsequently, tyrosine-phosphorylated peptides were enriched by immunoprecipitation and analyzed by LC-MS/MS.

Dataset Information

Pharmacophore and 3D-QSAR characterization of 6-arylquinazolin-4-amines as Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) inhibitors.

Publications

Pharmacophore and 3D-QSAR characterization of 6-arylquinazolin-4-amines as Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) inhibitors.

Similar Datasets

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