Deciphering The Synergy Mechanism From A Systems Pharmacology Perspective:Application To Gualou Xiebai Decoction For Coronary Heart Disease

Object: In this study,to dissect the synergic bioactive compounds from traditional Chinese medicine formula for coronary heart disease,Gualou Xiebai Decoction,a famous traditional Chinese medicine formula to confront coronary heart disease,is exemplified by employing a systems pharmacology strategy.Methods:(1)we screen out potential bioactive ingredients from Gualou Xiebai Decoction via ADME(absorption,distribution,metabolism and excretion).(2)The compound targeting is using similarity ensemble approach(SEA),weighted ensemble similarity(WES)algorithm and systematic drug targeting tool(SysDT).we perform the Gene Ontology(GO)enrichment analysis by linking the targets to DAVID.Through genetic enrichment analysis,a biological process network of active compounds was constructed.Combined with the TCMSP database,a target-disease information was obtained,thereby constructing a Target-Disease network.(3)In combination with the active compound and potential target information,a Target-Compound network is constructed.Coronary heart disease related proteins are extracted from TCMSP database and CTD.Establishing Disease Protein-Protein Interactions network(PPIs)by targeting's compounds.(4)The obtained human target proteins are gathered to be input into the Kyoto Encyclopedia of Genes and Genomes database to obtain the information of pathways.An incorporated ‘CHD-related pathway' is integrated in light of present cognition of coronary heart disease pathology.We utilized the targets as baits to fish corresponding pathways to construct a Target-pathway network.A relatively complete CHD-related pathway is manually assembled to further analyze the molecular synergy mechanisms.Results:(1)16 potential bioactive compounds are screened out by ADME evaluation.(2)By utilizing the target prediction methods,a total of 150 candidate targets were predicted.We performed the GO biological processes enrichment for these targets,and then found that many targets involved in hormone regulation,oxidation,and inflammation-related biological processes.Further,GO analysis of the promising targets showed that the GO term ‘proliferation and inflammatory response',‘metabolic regulation and oxidative stress' and ‘steroid-mediated and hormone-regulated' were predicted.For the target-disease network analysis,we implied that the Gualou Xiebai Decoction owned multi-target therapeutic efficiency in the treatment of coronary heart disease.(3)Through the topological analysis of the Target-Compound network: Among the bioactive ingredients,all of them regulated more than 18 targets,manifesting the potential synergistic effects among them.The disease PPIs network are divided into five functional clusters,where clusters were found to be closely related to coronary heart disease.The Probability Ensemble Approach(PEA)is used to predict potential drug combination pairs.(4)We exploited target-pathway network and CHD-related pathway analysis to dissect the synergistic mechanism and find the compound combinations act on multiple pathways involved in vascular smooth muscle contraction,insulin resistance and calcium signaling pathway,which indicated that the Gualou Xiebai Decoction formula may have a protective effect of myocardial injury caused by hyperglycemia.Conclusion: In summary,the integrated systems pharmacology method supplies accurate illustration of the molecular mechanisms of Gualou Xiebai Decoction to treat coronary heart disease and provides a new way for developing combination therapeutics.