Inhibition of GSK_3β by Iridoid Glycosides of Snowberry (Symphoricarpos albus) Effective in the Treatment of Alzheimer’s Disease Using Computational Drug Design Methods

Abstract

The inhibition of glycogen synthase kinase-3β (GSK-3β) activity prevents tau hyperphosphorylation and binds it to the microtubule network. Therefore, a GSK-3β inhibitor may be a recommended drug for Alzheimer’s treatment. In silico methods are currently considered as one of the fastest and most cost-effective available alternatives for drug/design discovery in the field of treatment. In this study, computational drug design was conducted to introduce compounds that play an effective role in inhibiting the GSK-3β enzyme by molecular docking and molecular dynamics simulation. The iridoid glycosides of the common snowberry (Symphoricarpos albus), including loganin, secologanin, and loganetin, are compounds that have an effect on improving memory and cognitive impairment and the results of which on Alzheimer’s have been studied as well. In this study, in the molecular docking phase, loganin was considered a more potent inhibitor of this protein by establishing a hydrogen bond with the ATP-binding site of GSK-3β protein and the most negative binding energy to secologanin and loganetin. Moreover, by molecular dynamics simulation of these ligands and GSK-3β protein, all structures were found to be stable during the simulation. In addition, the protein structure represented no change and remained stable by binding ligands to GSK-3β protein. Furthermore, loganin and loganetin have higher binding free energy than secologanin; thus, these compounds could effectively bind to the active site of GSK-3β protein. Hence, loganin and loganetin as iridoid glycosides can be effective in Alzheimer’s prevention and treatment, and thus, further in vitro and in vivo studies can focus on these iridoid glycosides as an alternative treatment.

Integrating transcriptome and chemical analyses to reveal the anti-Alzheimer’s disease components in Verbena officinalis Linn

“…The expression level of GSK-3β is related to the phosphorylation of tau protein. In the experiment, TWS119 was used as a positive control drug ( Eskandarzadeh et al, 2021 ). The NLRP3, BACE1, AChE, and GSK-3β are closely related to Alzheimer’s disease.…”

Interactions of Turmeric- and Curcumin-Functionalized Gold Nanoparticles with Human Serum Albumin: Exploration of Protein Corona Formation, Binding, Thermodynamics, and Antifibrillation Studies

“…These reductions in the fluctuation suggested the increase in stability of the residues in subdomain IIA and strong bonding to each other upon interaction with AuNPs. Other than that, no significant changes were observed in other regions of HSA, suggesting the preservation of the structure and function of the protein after conjugation with AuNPs …”

In silico study of alkaloids with quercetin nucleus for inhibition of SARS-CoV-2 protease and receptor cell protease

“…The Rg of the protein indicates the degree of compaction of the protein and a high increase in Rg values indicates instability in the system [ 44 , 53 ]. As shown in Fig 10 , the Rg value remained almost constant for all systems; however, the conformation of Mpro was affected by L₃, L₆, and L₇ due to their slight increase in Rg value ( Fig 10A ).…”

“…The calculation of the binding energy is important to analyze the binding affinity of inhibitors to the receptors. The g_mmpbsa program was used, which is described as: where ΔG complex , ΔG protein and ΔG ligand are the total MM-PBSA energy of the protein-ligand complex, solution-free energy of protein, and solution-free energy of ligand, respectively [ 44 , 45 ].…”