Interpret The Synergistic Mechanism of Shenfu Decoction in Treating Sick Sinus Syndrome From the Perspective of Systematic Pharmacology
Introduction: Sick sinus syndrome (SSS) is a common cardiovascular disease without available oral drugs for a long term routine treatment, which can be treated by Shenfu Decoction (SFD) according to Traditional Chinese Medicine (TCM) clinical applications. The purpose of this research is to decode the therapeutic mechanisms of SFD in treating SSS as well as interpret the synergistic relationship of herbs in SFD through the method of systematic pharmacology. Methods: We established a novel systematic pharmacological model, which integrate pharmacokinetic parameters, pharmacological data and network topology analysis, to effectively screen the key components of SFD. Based on the key components, gene ontology, pathway enrichment and molecular docking were used to clarify and validate the therapeutic mechanisms of SFD in treating SSS and the synergistic relationship of herbs in SFD. Results: Through our proposed mathematical model, we retrieved 55 components which were defined as synergistic functional components group (SFCG) from 209 potential active components of SFD screened by ADME parameters. Pathway analysis of SFCG targets indicated that RS and FZ could synergistically target to neuroactive ligand receptor reaction, cAMP signaling pathway, calcium signaling pathway, PI3K Akt signaling pathway, Rap1 signaling pathway and other pathways to treat SSS. Additionally, molecular docking analysis showed that the average affinity of SFCG and targets involved in the key pathways reached 6.36 kcal/mmol, validating the synergistic effect of RS and FZ in treating SSS. Conclusions: The therapeutic effect of SFD on SSS may be due to its functions of regulating ion channel function, signal transduction and energy metabolism. Besides, we found that the synergistic relationship between RS and FZ can be described at the levels of target, function and pathway.