Molecular docking studies and molecular dynamic simulation analysis: To identify novel ATP-competitive inhibition of...

The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer's disease (AD). 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 AD. GSK-3β activation or upregulation can contribute to neurodegeneration by promoting amyloid beta (Aβ) production and tau hyperphosphorylation. Whereas the underlying mechanism for abnormal production of GSK-3β in AD brains remains unclear.

Maestro was used, which is Schrodinger, for our computational simulation studies. In the present work, 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 Qikprop was used, for docking studies Glide module was used, Binding energy prediction the Prime was used and Molecular dynamic simulation (MDs) studies done using Desmond.

Our focus is mainly on an in-silico approach, focusing on library generation; first draw an IMID2 (imidazo [1,5-a]pyridine-3-carboxamide) 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, nine compounds were subjected to MDs studies.

Nine compounds showed good results with the most stable interactions. Among all the MD studies, the compound (Z3336252116) has shown good interaction and a good docking score. Further experiments and studies are required to confirm these results.