Computational Chemistry Research Group, Ton Duc Thang University, Ho Chi Minh City, Vietnam.
Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam.
PLoS One. 2018 Sep 18;13(9):e0204026. doi: 10.1371/journal.pone.0204026. eCollection 2018.
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.
淀粉样 β (Aβ) 肽的寡聚化被认为是阿尔茨海默病发展的关键致病因素。埃特萨莱特是一种非甾体抗炎口服药物（美国食品和药物管理局-独特成分标识符：653GN04T2G），此前有研究表明它在计算机上能很好地结合 Aβ肽的原纤维。在这里，使用温度复制交换分子动力学 (REMD) 模拟，在总共约 16.8 μs 的时间内进行了 48 个副本（每个副本 350 ns），对埃特萨莱特对可溶性 Aβ16-22 六聚体 (6Aβ16-22) 的寡聚化的影响进行了广泛研究。结果表明，埃特萨莱特可以进入 6Aβ16-22 构象的内部空间或结合在其表面，从而使六聚体不稳定。使用吸收、分布、代谢和排泄毒性 (preADMET) 预测工具预测埃特萨莱特能够穿过血脑屏障。总的来说，尽管这项研究是在低浓度试验抑制剂的情况下进行的，但研究结果表明，埃特萨莱特通过抑制 Aβ 寡聚体的形成，是一种有潜力的抗 AD 药物候选物，其平均结合自由能为-11.7 kcal/mol。
