Bioinformatics and Deep Learning Approach to Discover Food-Derived Active Ingredients for Alzheimer's Disease Therapy

Alzheimer's disease (AD) prevention is a critical challenge for aging societies, necessitating the exploration of food ingredients and whole foods as potential therapeutic agents. This study aimed to identify natural compounds (NCs) with therapeutic potential in AD using an innovative bioinformatics-integrated deep neural analysis approach, combining computational predictions with molecular docking and in vitro experiments for comprehensive evaluation. We employed the bioinformatics-integrated deep neural analysis of NCs for Disease Discovery (BioDeepNat) application in the data collected from chemical databases. Random forest regression models were utilized to predict the IC₅₀ (pIC₅₀) values of ligands interacting with AD-related target proteins, including acetylcholinesterase (AChE), amyloid precursor protein (APP), beta-secretase 1 (BACE1), microtubule-associated protein tau (MAPT), presenilin-1 (PSEN1), tumor necrosis factor (TNF)-α, and valosin-containing protein (VCP). Their activities were then validated through a molecular docking analysis using Autodock Vina. Predictions by the deep neural analysis identified 166 NCs with potential effects on AD across seven proteins, demonstrating outstanding recall performance. The top five food sources of these predicted compounds were black walnut, safflower, ginger, fig, corn, and pepper. Statistical clustering methodologies segregated the NCs into six well-defined groups, each characterized by convergent structural and chemical signatures. The systematic examination of structure-activity relationships uncovered differential molecular patterns among clusters, illuminating the sophisticated correlation between molecular properties and biological activity. Notably, NCs with high activity, such as astragalin, dihydromyricetin, and coumarin, and medium activity, such as luteolin, showed promising effects in improving cell survival and reducing lipid peroxidation and TNF-α expression levels in PC12 cells treated with lipopolysaccharide. In conclusion, our findings demonstrate the efficacy of combining bioinformatics with deep neural networks to expedite the discovery of previously unidentified food-derived active ingredients (NCs) for AD intervention.