Etersalate prevents the formations of 6Aβ16-22 oligomer: An in silico study

Abstract

Oligomerization of amyloid beta (Aβ) peptides has been considered as the crucially causative agent in the development of Alzheimer's disease. Etersalate, a nonsteroidal anti-inflammatory oral drug (United State Food and Drug Administration—Unique Ingredient Identifier: 653GN04T2G) was previously suggested to bind well to proto-fibrils of Aβ peptides in silico. Here, the effect of etersalate on the oligomerization of soluble Aβ16–22 hexamer (6Aβ16–22) were extensively investigated using temperature replica exchange molecular dynamics (REMD) simulations over ~16.8 μs in total for 48 replicas (350 ns per replica). The results reveal that etersalate can enter the inner space or bind on the surface of 6Aβ16–22 conformations, which destabilizes the hexamer. Etersalate was predicted to able to cross the blood brain barrier using prediction of absorption, distribution, metabolism, and excretion—toxicity (preADMET) tools. Overall, although the investigation was performed with the low concentration of trial inhibitor, the obtained results indicate that etersalate is a potential drug candidate for AD through inhibiting formation of Aβ oligomers with the average binding free energy of -11.7 kcal/mol.

Adequate prediction for inhibitor affinity of Aβ40protofibril using the linear interaction energy method

“…89 Observed results are in good consistent with previous studies that the Ab inhibitors favorably form domination of vdW interaction energy. 90,91 It also is in good consistent with the obtained 2-D protein-ligand interaction diagrams (Fig. S2 †) where the vdW interaction was found to dominate over the electrostatic interaction.…”

“…It should be emphasized that our groups have been successfully applied FEP and MM/PBSA to calculated binding free energy for various ligand-Ab peptides complexes. 64,66,91,94,95 When all of ligands are considered, the time-consuming FEP method, expected to give accurate binding affinity of proteinligand complex, generates results with a correlation to experimental data (R ¼ 0.72) similar to the LIE method with our parameter set (R ¼ 0.79). In contrast, the binding affinity calculated using MM/PBSA method gives a poor correlation with experiment data (R ¼ 0.27).…”

Atomistic investigation of an Iowa Amyloid-β trimer in aqueous solution

“…45 C a RMSD and R g were chosen as the coordinates as they were successfully used to obtain the FEL for other Ab peptide systems. [61][62][63] The FEL of solvated D23N 3Ab 11-40 is displayed in Fig. 5, which contains four minima centered at (RMSD; R g ) coordinates of (0.48; The selected structural parameters of these conformations are provided in Table 1.…”

In vitroandin silicodetermination of glutaminyl cyclase inhibitors

“…The simulation parameters were obtained by referring to previous publications. 40 In particular, GROMACS 5.1.3 (ref. 41) with GPGPU (general-purpose computing on graphics processing units) acceleration was employed to simulate the complexed hQC-ligand in solution.…”

“…49 The blood-brain barrier (BBB) crossing ability of a ligand was predicted using the PreADME protocol, 50 referring previous studies. 40,51 The human intestinal absorption capacity of a ligand was also estimated using the same application. 50…”