Screening Of Potential Drug For Alzheimer'S Disease: A Computational Study With Gsk-3 Beta Inhibition Through Virtual Screening, Docking, And Molecular Dynamics Simulation

The global impact of Alzheimer's disease (AD) necessitates intensive research to find appropriate and effective drugs. Many studies in AD suggested beta-amyloid plaques and neurofibrillary tangles-associated tau protein as the key targets for drug development. On the other hand, it is proved that triggering of Glycogen Synthase Kinase-3 beta (GSK-3 beta) also cause AD, therefore, GSK-3 beta is a potential drug target to combat AD. We, in this study, investigated the ability of small molecules to inhibit GSK-3 beta through virtual screening, Absorption, Distribution, Metabolism, and Excretion (ADME), induced-fit docking (IFD), molecular dynamics simulation, and binding free energy calculation. Besides, molecular docking was performed to reveal the binding and interaction of the ligand at the active site of GSK-3 beta. We found two compounds such as 6961 and 6966, which exhibited steady-state interaction with GSK-3 beta for 30 ns in molecular dynamics simulation. The compounds (6961 and 6966) also achieved a docking score of -9.05 kcal/mol and -8.11 kcal/mol, respectively, which is relatively higher than the GSK-3 beta II inhibitor (-6.73 kcal/mol). The molecular dynamics simulation revealed that the compounds have a stable state during overall simulation time, and lesser root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) values compared with co-crystal. In conclusion, we suggest the two compounds (6966 and 6961) as potential leads that could be utilized as effective inhibitors of GSK-3 beta to combat AD.[GRAPHICS].