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Keywords:

  • comparative molecular field analysis;
  • comparative molecular similarity indices analysis;
  • c-Jun N-terminal kinase;
  • molecular dynamics;
  • three-dimensional quantitative structure activity relationship

We report our three-dimensional quantitative structure activity relationship (3D-QSAR) studies of the series of anilinopyrimidine derivatives of JNK1 inhibitors. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied using different alignment methods. The ligand-based atom-by-atom matching alignment has produced better values for CoMFA (q= 0.646 and r= 0.983), while in CoMSIA it has achieved only lower statistical values. The pharmacophore-based model has produced (q= 0.568, r= 0.938) and (q= 0.670, r= 0.982) for CoMFA and CoMSIA models, respectively. As the model was based on the receptor-guided alignment, all the compounds were optimized within the receptor, resulting in q= 0.605 and r= 0.944 for CoMFA, and q= 0.587 and r= 0.863 for CoMSIA. Molecular Dynamic simulation studies suggested that the generated models were consistent with the low-energy protein ligand conformation. The CoMFA and CoMSIA contour maps indicated that the substitutions of the electropositive groups in the phenyl ring, and an addition of hydrophobic groups in the pyrimidine ring, are important to enhance the activity of this series. Moreover, the virtual screening analysis against NCI database yields potentials hits, and the results obtained would be useful to synthesize selective and highly potent c-Jun N-terminal kinase 1 analogs.