Research On The Molecular Mechanism Of Xiaoyaosan Against Alzheimer’s Disease Based On Network Pharmacology And Molecular Docking

ObjectiveThe network pharmacology and molecular docking were used to explore the mechanism of Xiaoyaosan intervention on AD at the molecular gene level and identify the possible targets and pathways,so as to provide a new direction for the experimental research of Xiaoyaosan in the prevention and treatment of AD and provide a scientific basis for its clinical application.MethodsPart I: Chemical components of eight drugs in Xiaoyaosan were retrieved using TCMSP database,and network pharmacology articles related to Xiaoyaosan were retrieved from databases such as How Net,Wanfang,Pubmed,China Biomedical Literature Service System（CBM）,and VIP,to supplement the missing key chemical components of Xiaoyaosan and to search for target genes of corresponding chemical components.The Uniprot protein database was used to search all human genes,and the drug target genes were input into the human gene table to match the Gene Symbol of the target genes of the chemical components using the vlookup function.Next,Cytoscape3.7.2 software was used to construct the "active ingredient-target" network of Xiaoyaosan,to clearly show the relationship between the active ingredients and target genes of Xiaoyaosan as well as between them.Then the databases of OMIM,Genecard and Drug Bank were used to retrieve AD-related genes,and the drug genes and AD target genes were intersected and input into the String database to construct PPI network.At the same time,topology attribute analysis was performed through the plug-in tool in Cytoscape3.7.2.Besides,GO enrichment analysis and KEGG Pathway analysis were performed using the Meta-scape platform,and the key pathways were obtained.Then the active components of Xiaoyaosan,AD disease targets,and key biological pathways were constructed into a network diagram using Cytoscape3.7.2,and the network analysis was performed to obtain topology attribute analysis data,where the first five key core protein targets and compound components were screened out.In the second part,the 3D structure of the compound was determined in the Pub Chem database,and the 3D structure corresponding to the gene target was downloaded in the RCSB PDB.Then,the ligands and protein required for the preparation of molecular docking were processed using Auto Dock Vina software,including removal of water molecules,hydrogenation,modification of amino acids,optimization of energy and adjustment of force field parameters.Finally,vina in pyrx software was used for docking,and Discovery Studio software was used to analyze and observe the docking results.Pymol was used to visualize the docking results and the 3D mode diagram was drawn.Results1.This study found that Xiaoyaosan mainly intervened the occurrence and development of AD disease through five key compounds such as quercetin,kaempferol,formononetin,β-sitosterol,and isorhamnetin through such targets as PTGS2,ESR1,AR,PPARG,and MAPK14.2.The biological processes that Xiaoyaosan mainly participates in in the prevention and treatment of AD include: cell reaction to nitrogen compounds,reaction to lipopolysaccharide,regulation of ion transport,positive regulation of cell death,aging,apoptosis signaling pathway,etc.Moreover,Xiaoyaosan can interfere with the disease progression of AD by regulating cancer pathway,lipid and atherosclerosis,MAPK signaling pathway,calcium ion pathway,cell aging,NF-κB pathway,cholinergic synapse and other signaling pathways.3.In this study,molecular docking was used to verify the good binding activity between AD key protein targets such as PTGS2,ESR1,AR,PPARG,and MAPK14 and the main pharmaceutical active components of Xiaoyaosan such as quercetin,kaempferol,formononetin,β-sitosterol,and isorhamnetin,and a stable docking complex could be formed.It could be seen that the main pharmaceutical active components of Xiaoyaosan could have a good matching and binding effect with AD disease targets.ConclusionThis study showed that the possible mechanisms of Xiaoyaosan intervention in AD were as follows: It regulated the cell response to nitrogen compounds,endotoxin lipopolysaccharide and ion transport through lipid and atherosclerosis pathways,calcium ion pathway,MAPK signaling pathway,and cell senescence and other multiple pathways,thus regulating Aβ deposition,Tau protein phosphorylation,oxidative stress response,inflammatory response and acetylcholine receptor,and then interfering with the AD process to improve the cognition and memory function of AD patients.