Computational screening for new neuroprotective ingredients against Alzheimer's disease from bilberry by cheminformatics approaches.

Bioactive ingredients from natural products have always been an important resource for the discovery of drugs for Alzheimer's disease (AD). Senile plaques, which are formed with amyloid-beta (Aβ) peptides and excess metal ions, are found in AD brains and have been suggested to play an important role in AD pathogenesis. Here, we attempted to design an effective and smart screening method based on cheminformatics approaches to find new ingredients against AD from (bilberry) and verified the bioactivity of expected ingredients through experiments. This method integrated advanced artificial intelligence models and target prediction methods to realize the stepwise analysis and filtering of all ingredients. Finally, we obtained the expected new compound malvidin-3-O-galactoside (Ma-3-gal-Cl). The experiments showed that Ma-3-gal-Cl could reduce the OH· generation and intracellular ROS from the Aβ/Cu/AA mixture and maintain the mitochondrial membrane potential of SH-SY5Y cells. Molecular docking and Western blot results indicated that Ma-3-gal-Cl could reduce the amount of activated caspase-3 binding with unactivated caspase-3 and reduce the expression of phosphorylated p38 binding with mitogen-activated protein kinase kinases-6 (MKK6). Moreover, Ma-3-gal-Cl could inhibit the Aβ aggregation binding with Aβ monomer and fibers. Thus, Ma-3-gal-Cl showed significant effects on protecting SH-SY5Y cells from Aβ/Cu/AA induced damage antioxidation effect and inhibition effect to the Aβ aggregation.