Molecular docking studies and molecular dynamic simulation analysis: To identify novel ATP-competitive inhibition of Glycogen synthase kinase-3β for Alzheimer’s disease

Abstract

Background The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer’s disease. The main pathological hallmarks of Alzheimer’s disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer’s disease. Methods We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond Results Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies. Conclusions Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.