The accumulation of amyloid β peptide<sub>1-42</sub> (Aβ<sub>1-42</sub>) masses in the brains of Alzheimer’s Disease (AD) patients is associated with neuronal loss and memory deficits. We ha...The accumulation of amyloid β peptide<sub>1-42</sub> (Aβ<sub>1-42</sub>) masses in the brains of Alzheimer’s Disease (AD) patients is associated with neuronal loss and memory deficits. We have previously reported that oral administration of docosahexaenoic acid (DHA, C22:6, n-3) significantly decreases Aβ burden in the brains of AD model rats and that direct in vitro incubation of DHA with Aβ<sub>1-42</sub> curbs the progression of amyloid fibrillation. In the present in silico study, we investigated whether DHA computationally binds with amyloid peptides. The NMR solution structures of Aβ<sub>1-42</sub> were downloaded from the Protein Data Bank (PDB IDs: 1Z0Q and 2BEG). The binding of DHA to Aβ peptides was assessed by molecular docking using both a flexible and rigid docking system. Thioflavin T (ThT) was used as positive control. The chemical structures of ThT and DHA were modeled and converted to the PDB format using PRODRUG. Drug-like properties of DHA were evaluated by ADME (Absorption, Distribution, Metabolism, and Excretion). DHA was found to successfully dock with Aβ<sub>1-42</sub>. Computational analyses of the binding of DHA to Aβ<sub>1-42</sub>, as evaluated by docking studies, further corroborated the inhibitory effect of DHA on in vitro Aβ<sub>1-42</sub> fibrillogenesis and might explain the in vivo reduction of amyloid burden observed in the brains of DHA-administered AD model rats demonstrated in our previous study. These computational data suggest the potential utility of DHA as a preventive medication in Aβ-induced neurodegenerative diseases, including AD.展开更多
文摘The accumulation of amyloid β peptide<sub>1-42</sub> (Aβ<sub>1-42</sub>) masses in the brains of Alzheimer’s Disease (AD) patients is associated with neuronal loss and memory deficits. We have previously reported that oral administration of docosahexaenoic acid (DHA, C22:6, n-3) significantly decreases Aβ burden in the brains of AD model rats and that direct in vitro incubation of DHA with Aβ<sub>1-42</sub> curbs the progression of amyloid fibrillation. In the present in silico study, we investigated whether DHA computationally binds with amyloid peptides. The NMR solution structures of Aβ<sub>1-42</sub> were downloaded from the Protein Data Bank (PDB IDs: 1Z0Q and 2BEG). The binding of DHA to Aβ peptides was assessed by molecular docking using both a flexible and rigid docking system. Thioflavin T (ThT) was used as positive control. The chemical structures of ThT and DHA were modeled and converted to the PDB format using PRODRUG. Drug-like properties of DHA were evaluated by ADME (Absorption, Distribution, Metabolism, and Excretion). DHA was found to successfully dock with Aβ<sub>1-42</sub>. Computational analyses of the binding of DHA to Aβ<sub>1-42</sub>, as evaluated by docking studies, further corroborated the inhibitory effect of DHA on in vitro Aβ<sub>1-42</sub> fibrillogenesis and might explain the in vivo reduction of amyloid burden observed in the brains of DHA-administered AD model rats demonstrated in our previous study. These computational data suggest the potential utility of DHA as a preventive medication in Aβ-induced neurodegenerative diseases, including AD.
