Abstract
The purpose of our study is to identify phosphorylated tau (p-tau) inhibitors. P-tau has recently received great interest as a potential drug target in Alzheimer’s disease (AD). The continuous failure of Aβ-targeted therapeutics recommends an alternative drug target to treat AD. There is increasing evidence and growing awareness of tau, which plays a central role in AD pathophysiology, including tangles formation, abnormal activation of phosphatases/kinases, leading p-tau aggregation in AD neurons. In the present study, we performed computational pharmacophore models, molecular docking, and simulation studies for p-tau in order to identify hyperphosphorylated sites. We found multiple serine sites that altered the R1/R2 repeats flanking sequences in the tau protein, affecting the microtubule binding ability of tau. The ligand molecules exhibited the p-O ester scaffolds with inhibitory and/or blocking actions against serine residues of p-tau. Our molecular docking results revealed five ligands that showed high docking scores and optimal protein-ligand interactions of p-tau. These five ligands showed the best pharmacokinetic and physicochemical properties, including good absorption, distribution, metabolism, and excretion (ADME) and admetSAR toxicity tests. The p-tau pharmacophore based drug discovery models provide the comprehensive and rapid drug interventions in AD, and tauopathies are expected to be the prospective future therapeutic approach in AD.
Highlights
Alzheimer’s disease (AD) is a devastating mental illness with an irreversible progressive brain disorder that slowly destroys memory skills and learning abilities
The non-availability models required requiredus ustotobuild buildaamodel model based on template based protein modeling (TBM)
The modeled tau protein evaluations were done with the SAVES server, which showed the best consistency with RAMPAGE (Ramachandran plot) results
Summary
Alzheimer’s disease (AD) is a devastating mental illness with an irreversible progressive brain disorder that slowly destroys memory skills and learning abilities. AD is the sixth leading cause of death in the United States [1]. It seems likely that damage to the brain starts a decade or more before the memory and other cognitive problems appear. AD progression stages vary from mild to severe in middle age people to older persons detected with cognitive tests [3]. The pathophysiology of AD features abnormal accumulation of amyloid beta (Aβ) and phosphorylated tau (P-tau) throughout the brain, which causes healthy neurons to malfunction with synaptic damage and neuronal dysfunction, leading to neuronal death and cognitive decline in elderly persons [4,5]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have