Identifying Active Compounds and Mechanisms of Citrus changshan-Huyou Y. B. Chang against URTIs-Associated Inflammation by Network Pharmacology in Combination with Molecular Docking

Abstract

Purpose. The ripe fruits of Citrus changshan-huyou, known as Quzhou Fructus Aurantii (QFA), have been commonly used for respiratory diseases. The purpose of this study was to investigate their active compounds and demonstrate their mechanism in the treatment of upper respiratory tract infections (URTIs) through network pharmacology and molecular docking. Methods. The prominent compounds of QFA were acquired from TCMSP database. Their targets were retrieved from SwissTargetPrediction database, and target genes associated with URTIs were collected from DisGeNET and GeneCards databases. The target protein-protein interaction (PPI) network was constructed by using STRING database and Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were enriched. Visual compound-target-pathway network was established with Cytoscape. The effects of compounds were verified on the inhibitory activities against phosphoinositide 3-kinases (PI3Ks). Finally, the molecular docking was carried out to confirm the binding affinity of the bioactive compounds and target proteins. Results. Five important active compounds, naringenin (NAR), tangeretin (TAN), luteolin (LUT), hesperetin (HES), and auraptene (AUR), were obtained. The enrichment analysis demonstrated that the pathways associated with inflammation mainly contained PI3K/Akt signalling pathway, TNF signalling pathway, and so on. The most important targets covering inflammation-related proteins might be PI3Ks. In vitro assays and molecular docking exhibited that TAN, LUT, and AUR acted as PI3Kγ inhibitors. Conclusion. The results revealed that QFA could treat URTIs through a multi-compound, multi-target, multi-pathway network, in which TAN, LUT, and AUR acted as PI3Kγ inhibitors, probably contributing to a crucial role in treatment of URTIs.