Development of Dual-Target Protein Kinase Inhibitors for Tau Hyperphosphorylation in Alzheimer's Disease

Alzheimer's disease (AD) is a chronic neurodegenerative disease with a course of progressive cognitive dysfunction, failure of synapses functions, and a loss of neurons; mostly related to the deposition of amyloid-β plaques (Aβ) and hyperphosphorylation of tau protein. Glycogen Synthase Kinase-3β (GSK-3β) and Cyclin-Dependent Kinase-5 (CDK5) are important kinases involved in tau-related processes: promoting neurofibrillary tangle formation and neuronal degeneration, respectively. In the present study, a series of inhibitors of GSK-3β and CDK5 were screened to identify new dual-target inhibitors for AD treatment, focusing on the ability to inhibit hyperphosphorylation of tau.In the present study the ability of a series of GSK-3β and CDK5 inhibitors to inhibit hyperphosphorylation of tau was assessed and has led to the identification of novel dual-target inhibitors as potential therapeutic candidates for the care of tau hyperphosphorylated in AD. A computational integrated approach to drug discovery, including protein modeling and preparation, high throughput virtual screening, sequential dual docking, molecular dynamics simulation, binding free energy prediction and ADMET prediction, was used in the process. To optimize the X-ray crystal structure for docking studies, X-ray crystal structures of GSK-3β and CDK5 were taken from PDB are shown in figure graphical abstract. Ambiguity Library of structurally diverse ligands was screened against both kinase targets to search for high structure similarity for two targets, meaning compounds with strong dual inhibitory activity. Out of the shortlisted molecules, Compounds 08, 09, 05, and 10 showed very good docking scores along with stable hydrogen bonding interactions and good hydrophobic contacts with the ATP-binding pockets of the both kinases. The structural stability and stability of protein–ligand interactions under physiological conditions were confirmed by molecular dynamics simulation and the binding free energies were calculated with MM-PBSA with good scores. In silico studies including ADMET and permeability across blood–brain barrier also showed that chosen compounds had good pharmacokinetics, CNS permeability, metabolic stability, and had low predicted toxicity. The identified dual inhibitors showed highly promising potential to inhibit tau hyperphosphorylation by targeting both GSK-3β and CDK5 and provide a potential multi-target based therapeutic approach to Alzheimer's disease. The findings suggest that the identified lead compounds are worth further testing and optimization and could be used to create effective anti-Alzheimer drugs.