In Silico Prediction Studies of Diphenyline Ketone Derivatives As Potent Modulators of Glycogen Synthase Kinase-3β

Abstract

Background: Glycogen synthase kinase (GSK) -3β is a serine/threonine kinase that phosphorylates and inactivates glycogen synthase. GSK-3β is involved in various downstream signalling transductions resulting in cellular proliferation, migration, glucose regulation and apoptosis. Regulation of GSK-3β is also so critical in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Multiple sclerosis. Thus blocking the active site of GSK-3β with potent modulators may rescue neuron loss due to apoptosis.

Aim: The aim of this study was to predict the binding affinity of twelve selective diphenyline ketone derivatives at the active site gorge of GSK-3β.

Methods: Molecular docking and dynamic simulation study was performed using Schrodinger Molecular modelling software package (Schrodinger, LLC).

Results: The docking score of co-crystallised ligand such as i-3 monoxime (PDB code: 1Q41), AMP-PNP (PDB code: 1PYX), staurosporine (PDB code: 1Q3D), and alsterpaullone (PDB code: 1Q3W) was found to be -8.99,-7.91,-4.51 and -6.14 kcal/mol respectively. For the 12 test compounds, a total of 64 conformers were generated using ligprep and glide docking score of best conformer (Compound 6) was found to be -8.22 kcal/mol. In addition, the stability of protein-ligand complex was determined by molecular dynamic simulation studies at time duration of 50 nsec. The values of root mean square deviation (RMSD, Å) and root mean square fluctuation (RMSF, nm) were used to determine the strength of protein–ligand complex.

Conclusion: In silico molecular docking and dynamic simulation studies predicted that diphenyline ketone derivatives exhibit a greater binding affinity than reference ligand. In future, in-vitro and in-vivo studies will be carried out in order to explain the pharmacology of diphenyline ketone derivatives in modulating GSK-3β activity in neurodegenerative diseases.

Keywords: In silico,diphenyline ketone derivatives,glycogen synthase kinase-3β

JEL Classification: [comma,seprated]