In silico design novel (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine derivatives as inhibitors for glycogen synthase kinase 3 based on 3D-QSAR, molecular docking and molecular dynamics simulation.

Glycogen Synthase Kinase 3 (GSK-3) is a member of cellular kinase with various functions, such as glucose regulation, cellular differentiation, neuronal function and cell apoptosis. It has been proved as an important therapeutic target in type 2 diabetes mellitus and Alzheimer's disease. To better understand their structure-activity relationships and mechanism of action, an integrated computational study, including three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD), was performed on 79 (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine GSK-3 inhibitors. In this paper, we constructed 3D-QSAR using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) method. The results showed that the CoMFA model (q2 = 0.743,  r2 = 0.980) and the CoMSIA model (q2 = 0.813,  r2 = 0.976) had stable and reliable predictive ability. The electrostatic and H-bond donor fields play important roles in the models. The contour maps of the model visually showed the relationship between the activity of compounds and their three-dimensional structure. Molecular docking was used to identify the key amino acid residues at the active site of GSK-3 and explore its binding mode with ligands. Based on 3D-QSAR models, contour maps and the binding feature between GSK-3 and inhibitor, we designed 10 novel compounds with good potential activity and ADME/T profile. Molecular dynamics simulation results validated that Ile62, Val70 and Lys85 located in the active site play a key role for GSK-3 complexed with inhibitors. These results might provide important information for designing GSK-3 inhibitors with high activity.

He Q ，Han C ，Li G ，Guo H ，Wang Y ，Hu Y ，Lin Z ，Wang Y ... -  《-》

In silico approaches to develop new phenyl-pyrimidines as glycogen synthase kinase 3 (GSK-3) inhibitors with halogen-bonding capabilities: 3D-QSAR CoMFA/CoMSIA, molecular docking and molecular dynamics studies.

Cabezas D ，Mellado G ，Espinoza N ，Gárate JA ，Morales C ，Castro-Alvarez A ，Matos MJ ，Mellado M ，Mella J ... -  《-》

3D-QSAR and molecular docking studies on pyrazolopyrimidine derivatives as glycogen synthase kinase-3beta inhibitors.

Dessalew N ，Patel DS ，Bharatam PV 《-》

Molecular modeling studies to characterize N-phenylpyrimidin-2-amine selectivity for CDK2 and CDK4 through 3D-QSAR and molecular dynamics simulations.

Chohan TA ，Chen JJ ，Qian HY ，Pan YL ，Chen JZ ... -  《-》

In silico design of novel FAK inhibitors using integrated molecular docking, 3D-QSAR and molecular dynamics simulation studies.

Shirvani P ，Fassihi A 《-》