Deciphering the pharmacological mechanism of the Chinese formula Huanglian-Jie-Du decoction in the treatment of ischemic stroke using a systems biology-based strategy

Aim： Huanglian-Jie-Du decoction （HUDD） is an important multiherb remedy in TCM, which is recently demonstrated to be effective to treat ischemic stroke. Here, we aimed to investigate the pharmacological mechanisms of HUDD in the treatment of ischemic stroke using systems biology approaches. Methods： Putative targets of HUDD were predicted using MetaDrug. An interaction network of putative HLIDD targets and known therapeutic targets for the treatment of ischemic stroke was then constructed, and candidate HUDD targets were identified by calculating topological features, including ＇Degree＇, ＇Node-betweenness＇, ＇Closeness＇, and ＇K-coreness＇. The binding efficiencies of the candidate HLJDD targets with the corresponding compositive compounds were further validated by a molecular docking simulation. Results： A total of 809 putative targets were obtained for 168 compositive compounds in HUDD. Additionally, 39 putative targets were common to all four herbs of HUDD. Next, 49 major nodes were identified as candidate HUDD targets due to their network topological importance. The enrichment analysis based on the Gene Ontology （GO） annotation system and the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway demonstrated that candidate HLJDD targets were more frequently involved in G-protein-coupled receptor signaling pathways, neuroactive ligand-receptor interactions and gap junctions, which all played important roles in the progression of ischemic stroke. Finally, the molecular docking simulation showed that 170 pairs of chemical components and candidate HUDD targets had strong binding efficiencies. Conclusion： This study has developed for the first time a comprehensive systems approach integrating drug target prediction, network analysis and molecular docking simulation to reveal the relationships between the herbs contained in HUDD and their putative targets and ischemic stroke-related pathways.