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

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

  • J Biomol Struct Dyn. 2021 Nov;39(18):7065-7079. doi: 10.1080/07391102.2020.1805362.
Nandha Devi Elangovan 1 Anantha Krishnan Dhanabalan 2 Krishnasamy Gunasekaran 2 3 Ramesh Kandimalla 4 5 Devaraj Sankarganesh 6 7
Affiliations

Affiliations

  • 1 Department of Bioinformatics, Stella Maris College, Chennai, India.
  • 2 Center of Advanced Study in Crystallography and Biophysics, University of Madras, Chennai, India.
  • 3 Bioinformatics Infrastructure Facility, University of Madras, Chennai, India.
  • 4 Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
  • 5 Department of Biochemistry, Kakatiya Medical College, Warangal, India.
  • 6 Department of Biotechnology, School of Bio and Chemical Engineering, Kalasalingam Academy of Research and Education, Krishnankoil, India.
  • 7 Department of Microbial Biotechnology, Bharathiar University, Coimbatore, India.
Abstract

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.

Keywords

AD; GSK-3β; binding free energy calculation; compound 6961; induced-fit docking; molecular dynamics simulation; virtual screening.

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