Deciphering the pharmacological mechanism of the Chinese formula huanglian-jie-du decoction in the treatment of ischemic stroke using a systems biology-based strategy.
OBJECTIVE
Huanglian-jie-du decoction (HLJDD) 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 HLJDD in the treatment of ischemic stroke using systems biology approaches.


METHODS
Putative targets of HLJDD were predicted using MetaDrug. An interaction network of putative HLJDD targets and known therapeutic targets for the treatment of ischemic stroke was then constructed, and candidate HLJDD 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 HLJDD. Additionally, 39 putative targets were common to all four herbs of HLJDD. Next, 49 major nodes were identified as candidate HLJDD 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 HLJDD targets had strong binding efficiencies.


CONCLUSIONS
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 HLJDD and their putative targets and ischemic stroke-related pathways.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Yan-qiong
YQ
Zhang
1] Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China [2] School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China.
Song-song
SS
Wang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Wei-liang
WL
Zhu
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Yan
Y
Ma
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Fang-bo
FB
Zhang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Ri-xin
RX
Liang
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Hai-Yu
HY
Xu
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Hong-jun
HJ
Yang
D000818:Animals; D002545:Brain Ischemia / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D057225:Data Mining; D030541:Databases, Genetic; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D023281:Genomics; D006801:Humans; D008516:Medicine, Chinese Traditional / Q000379:methods*; D062105:Molecular Docking Simulation; D060066:Protein Interaction Maps; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D049490:Systems Biology / Q000379:methods*; D018511:Systems Integration; D016896:Treatment Outcome; D057188:Workflow
D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; C000605453:huanglian-jie-du decoction