Screening of potential drug for Alzheimer's disease: a computational study with GSK-3 β inhibition through virtual screening, docking, and molecular dynamics simulation

• Published in: Journal of biomolecular structure & dynamics Vol. 39; no. 18; pp. 7065 - 7079
• Main Authors: Elangovan, Nandha Devi, Dhanabalan, Anantha Krishnan, Gunasekaran, Krishnasamy, Kandimalla, Ramesh, Sankarganesh, Devaraj
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 12.12.2021
• Subjects: Alzheimer Disease - drug therapy; binding free energy calculation; compound 6961; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; GSK-3β; Humans; induced-fit docking; Molecular Docking Simulation; Molecular Dynamics Simulation; virtual screening; GSK-3β; induced-fit docking; AD; compound 6961; virtual screening; molecular dynamics simulation; binding free energy calculation
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2020.1805362

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-3β (GSK-3β) also cause AD, therefore, GSK-3β is a potential drug target to combat AD. We, in this study, investigated the ability of small molecules to inhibit GSK-3β 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-3β. We found two compounds such as 6961 and 6966, which exhibited steady-state interaction with GSK-3β 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-3β 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-3β to combat AD. Communicated by Ramaswamy H. Sarma