Systems pharmacology-based drug discovery from Amaryllidaceae alkaloids and investigation of mechanisms of action in treatment of Alzheimer's disease.

Objectives: Given the success of galanthamine in treating Alzheimer's disease, this study aims to establish an effective method to find drugs from Amaryllidaceae alkaloids and to clarify its mechanism in treating Alzheimer's disease.

Methods: The pharmacodynamic basis and mechanism of action between Amaryllidaceae alkaloids and Alzheimer's disease were explored by constructing a compound-target-disease network, targets protein-protein interaction, gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and molecular docking verification.

Key Findings: In total, a chemical library of 357 potential alkaloids was constructed. A total of 100 active alkaloid components were identified. Thirty-nine associated targets were yielded based on network construction, and the key targets were defined as HSP90AA1, ESR1, NOS3, PTGS2, and PPARG using protein-protein interaction network. Gene ontology items (490) and 68 Kyoto Encyclopedia of Genes and Genomes pathways were selected through the enrichment of target functions, including neuroactive ligand-receptor interaction, calcium signaling pathway, cAMP signaling pathway, Alzheimer disease, and serotonergic synapse that were related to Alzheimer's disease. Lastly, molecular docking demonstrated good stability in combining selected alkaloids with targets.

Conclusions: This study explained the mechanisms of Amaryllidaceae alkaloids in preventing and treating Alzheimer's disease and established a novel strategy to discover new drugs from biological chemical sources.