QSAR modeling, molecular docking, ADMET prediction and molecular dynamics simulations of some 6-arylquinazolin-4-amine derivatives as DYRK1A inhibitors

Abstract

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase with diverse functions in neuronal development and adult brain physiology. QSAR study was performed for a diverse set of thirty-three6-arylquinazolin-4-amine derivatives as DYRK1A inhibitors. The QSAR model with HOMO, LUMO, qCsub, SAG and MW descriptors showed satisfactory internal and external validation parameters (Rtrain2=0.867,Radj2=0.831, QLOO2= 0.755,F=24.682 andRpred2 =0.856). The excellent statistical results obtained for the developed model, strongly suggest that the model is reasonable for the prediction of the activity of new inhibitors. Therefore, we have designed several new potent DYRK1A inhibitors and validated their inhibitory activity by molecular docking methods using Autodock tools. Based in silico analysis, two novel compounds N2 and N11have been designed, which they have been identified hydrophobic and hydrogen bonds, with the binding pockets of active site4YLJ. Furthermore, the two newly designed compounds exhibited good ADMET properties, their molecular dynamics studies have shown a favorable energetic state and dynamic stability, characterized by root mean square deviation (RMSD), root mean square fluctuation (RMSF) and hydrogen bond. The outcomes of this study can be used to show the interest of DYRK1A inhibition for Alzheimer treatment.