Advancing Alzheimer’s therapeutics via in silico strategies: Tideglusib based multi-target analogues

Abstract

Alzheimer’s disease is an advanced neurodegenerative illness that disturbs cognitive behavior. Multiple factors are responsible for the etiology of Alzheimer’s disease and one of the cores neuropathologic finding is generation of hyper-phosphorylated tau. GSK-3β or Glycogen synthase kinase-3β a kinase leads to the hyperphosphorylation of tau protein at multiple sites and aggregates into neurofibrillary tangles in AD patient’s brain. Tideglusib is a drug which is under second phase of clinical trial (NCT01350362), impedes the GSK-3β at therapeutically concentration that has been established through various in silico techniques like scaffold morphing, pharmacokinetic, molecular docking and dynamic simulations studies. The Tideglusib based analogues showed good interactions with the catalytic dyed residue (Cys199) of GSK-3β GSK-3β, the main amino acid responsible for its tau hyperphosphorylation activity. Also, the designed analogues of Tideglusib are analyzed for its Multi targeting potential with three main receptors (GSK-3β, AChE, BACE) through molecular docking and molecular dynamic simulation approaches. SG-09 stands out with the best binding affinity and the stable ligand-protein interaction analogues in the time interval of 100 ns can be used as Multitargeting drug with further in silico, in vitro and in vivo clinical evaluation. This design strategy could thus reap considerable clinical and economic rewards.