Towards Synergistic Integration Mechanism Analysis Of Traditional Chinese Medicine From The Target Network Perspective

Traditional Chinese medicine(TCM)is a major part of Chinese medicine,which emphasizes treating diseases from a systems and holistic perspective.To systematically clarify the molecular mechanisms of TCM is of great significance for promoting the modernization of Chinese medicine and the development of modern medicine.The overall efficacy of TCM is the result of multiple chemical components interacting with multiple targets to form a complex drug-target network,and perturbing multiple pathways and functional modules to produce synergistic and integrative effects.Therefore,revealing the scientific essence of TCM has become the most urgent task of Chinese medicine research.To this end,this study starts from the targets of the TCM compounds,to explore the synergistic and integrative effects of these targets,resulting in elucidating its overall mechanisms of action.The study mainly includes the following steps: combining the computational technology and biological data to develop a direct target prediction algorithm which is in accordance with the characteristics of TCM,so as to reveal the targets of TCM compounds.Based on this target prediction method,the multi-level synergistic effect of the target network is explored.In addition,the functional modules of the target network and the mechanisms of the multi-pathway regulation of the disease are also explored on a larger interactome-scale.Specific contents include:(1)To identify drug-target direct interactions on a large scale,we put forward the hypothesis that the ensemble features of the ligand group can accurately reflect the direct binding information of a certain target based on ligand-target interaction data and establish the weighted ensemble similarity(WES)model.WES includes: a)we construct 98,327 drug-taget interactions by retrieving different data sources;b)identifying the key ligand structural features that are highly-related to the pharmacological properties in a framework of ensemble;c)determining a drug’s affiliation of a target by evaluation of the overall similarity(ensemble)rather than a single ligand judgment;and d)integrating the standardized ensemble similarities(Z score)by Bayesian network and multi-variate kernel approach to make predictions.All these lead WES to predict drug direct targets with external and experimental test accuracies of 70% and 71%,respectively.This shows that the WES method provides a potential in silico model for drug repositioning and discovery.(2)Based on the above direct target prediction algorithm,we take the Huangqin Zhizi formula as an example to explore the synergistic effect among multiple pathways and multiple layers of TCM from the perspective of target netwok.The primary findings of the study can be summarized as follows: a)We capture 212 potential active ingredients by evaluating the druglikeness of compounds in Huangqin Zhizi;b)Utilizing these lead compounds as probes,we predict 122 targets by WES algorithm,and further in vitro experiments confirm the reliability of the direct compound-target interactions;c)Compound-target and target-pathway network associative analysis illustrate the complex linkage between disease macroscopic phenotype and microcosmic molecules such as compounds,targets and pathways,and select out multiple target-releated pathways,such as Toll-like receptor signaling pathway and Jak-STAT signaling pathway;d)An integrated pathway is built with targets as bridges,which displays that Huangqin Zhizi formula is effective in the treatment of BVD by inhibiting inflammation,enhancing immune responses in hosts toward virus infection;e)Molecular function,cellular component and biological processes analysis of targets disclose the regulation action of TCM under the multi-level network system.(3)We take erchen decoction as probes to trace the interactions across multiple targets and explore the functional modules of the target netwrk for the treatment of diseases.The main results are as follows: a)The 126 lead compounds are screened by pharmacological evaluation and further comparison of chemical properties confirms that these compounds have the potential to develop into new drugs;b)With the aid of the WES model,we gain 448 targets of the formula and infer the direct compound-target connections to understand how compounds work on a specific target;c)We identify 11 modules with specific biological functions by heterogeneous network convergence and modularization analysis,which clarifies the cooperative adjustment of the TCM target network.To sum up,this study focus on identifying the targets of TCM and clarifying their roles in the molecular network,to reveal the synergistic effect of TCM.A direct target prediction model is established to meet the characteristics of TCM.The model can quickly and effectively identify the target proteins of TCM compounds,which provides a new tool for both TCM mechanisms research and new drug discovery.Based on this method,this study used two formulas,Huangqin Zhizi and Erchen Decoction,as examples to clarify their multi-pathway,multi-level,multi-link synergistic effect through predicting and analyzing the targets and target networks/pathways of the formula,which provides a new reference for understanding the holistic mechanism of TCM.