Relative Binding Free Energy Computation of GSK-3β Kinase-Ligand Complexes Using Thermodynamic Integration MD Simulation: Compounds with Pyrazolo-Pyridazin Fused Ring

• Main Authors: Hsu, Wen-Chi, 許文綺
• Other Authors: Sun, Ying-Chieh
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/565ht6

碩士 === 國立臺灣師範大學 === 化學系 === 103 === Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase that plays an important role in the pathogenesis of Alzheimer's disease (AD). It was postulated that when GSK-3β kinase’s activity is too high, it over-phosphorylates tau protein and causes AD.Inhibition of GSK-3βkinase would provide therapeutic effect in alleviated and/or cure AD.In the present study, we used thermodynamic integration molecular dynamics (TI-MD) simulation to calculate protein-ligand binding free energy to aid in design of GSK-3β inhibitors. First, we computed the affinity of analogous GSK-3β kinase inhibitors of available experimental data and the computed results were in reasonably good agreement with the experimental value.Subsequently, we employed the same protocol in order to identify new analogous inhibitors which would be recommended for kinase experiment. We presented predicted results of relative binding free energy ΔΔG (kcal/mol) for 11 compounds. Three analogs PP1, PP2 and LL4 were found to be effective inhibitors in kinase assay experiment.In addition, the binding modes of these 3 compounds were investigated. It was found that the LL4 adopted binding mode similar to ZRM's but PP1 and PP2 is adopted different binding modes. The computed ΔΔG values of PP1,PP2 and LL4 were 5.1, 2.7, and 1.2 kcal/mol , correlating well with experiment data of 3.7, 0.7, and -0.4 kcal/mol, respectively. The correlation coefficient (R2) was 0.83. Analysis of interactions between ligands and GSK-3β kinase suggested that addition the hydrophilic group at the site of the functional group pointing towards water can enhance the binding affinity of lignad-protein binding. These results provide useful insight for further design of GSK-3β kinase inhibitors in the future.