Research On Core Drug Excavation And Mechanism Of Type 2 Diabetes Based On Complex Network

Type 2 diabetes mellitus is a type of diabetes associated with insulin resistance and insufficient insulin secretion.The incidence of type 2 diabetes is increasing year by year,but there is no specific treatment.Traditional Chinese medicine(TCM)has accumulated rich experience in the prevention and treatment of type 2 diabetes,has a large number of resources and has great advantages,but its components are numerous,its function is complex,and its mechanism is not clear.It lacks the study in the view of the combination from the system and the macro and microcosmic,which limits the application in the field of TCM in treating type 2 diabetes.With the development and progress of computer information science,it is very important to use new technology,new methods to solve existing problems and explore the mechanism of the onset of complex diseases.Therefore,it is of theoretical significance and practical value to study the type 2 diabetes mellitus from the perspective of complex network.Objective1.To explore the core Chinese medicine herbs for treating type 2 diabetes mellitus based on complex network through analyzing of the network structure and the rules of medication.2.In view of the core treatment of type 2 diabetes mellitus,we screened the main active ingredients and predicted the targets of active components.After that,the mechanism of the treatment of type 2 diabetes was discussed from the multi-level and multi-angle of "drug-component-target-pathway" by using the network pharmacology research method.3.A molecular docking experiment was carried out on the potential target of treating type 2 diabetes with the core Chinese herbal medicine to reveal the pharmacological mechanism and the key link of traditional Chinese medicine in type 2 diabetes mellitus from microcosmic level.Methods1.This article took type 2 diabetes mellitus as the research object,and all published literatures about TCM treatment of type 2 diabetes were obtained by computer retrieval.Databases searched were China National Knowledge Infrastructure Database(CNKI),theChongqing VIP Chinese Science and Technology Periodical Database(VIP),Wan Fang Data and PubMed Database.Through inclusion and exclusion criteria,we got the prescription data set of Chinese medicine for treating type 2 diabetes.According to the statistics of the frequency of herb usage and the distribution of the syndrome types,we calculated the topological property parameters of the medicine network,analyzed the structure of the core network and the compatibility rule of Chinese medicine,and then explored the characteristics of TCM treatment of type 2 diabetes mellitus with the association rules algorithm to find the potential core prescriptions of TCM treatment for type 2 diabetes mellitus.2.According to the above results,by searching each database,we used reverse targeting for core Chinese herbs based on the ligand,and the target of drug prediction was obtained according to the matching value of the pharmacodynamic group.At the same time,the targets of disease were searched,and the targets of drug prediction were mapped to them.After that,the potential targets of TCM in treating type 2 diabetes were obtained.Based on the data set of traditional Chinese medicine compounds and type 2 diabetes related targets data set,the"disease-Traditional Chinese medicine-target","target-target" and so on were made to establish the complex relationship network of the core herb of type 2 diabetes using software Cytoscape3.5.1 to visualize the above data,and to describe and analyze the whole network.Last,the gene function and channel enrichment of potential targets were analyzed by related tools.3.Taking Discovery Studio software as the carrier,the small molecular structures of the core traditional Chinese herbs were introduced into the software to preprocess,including two-dimension turned to three-dimensional,structural transformation,structural optimization,standardization and hydrogenation.At the same time,we downloaded the crystal structure of each core target protein from the PDB database,then imported them to Discovery Studio,after that we removed the water molecule from the protein and defined the active sites.Then,the CDocker algorithm of semi flexible molecular docking was used to combine the small molecules of Chinese medicine with the receptor proteins.According to the scoring function,the results were screened and sorted,and the binding modes of the small molecule conformation and receptor protein were analyzed.Results1.Through the selection and collation of the related literatures on the treatment of type 2 diabetes mellitus of traditional Chinese medicine,this study included 369 literatures and a total of 444 prescriptions.After statistics on the type and herb use of traditional Chinese medicine prescriptions included in the literature,it was found that the main TCM syndromes of type 2 diabetes mellitus involved deficiency of qi and yin,yin deficiency and heat flourishing,stagnation of blood stasis,damp of dampness and phlegm and blood stasis,in which the deficiency of qi and yin accounted for the largest proportion and accounted for 44.44%of all types of syndromes.The results showed that the commonly used therapeutic herbs were HuangQi,ShanYao,ShengDiHuang,DanShen,GeGen,FuLing,HuangLian,TianHuaFen,MaiDong and so on,involved tonifying qi,nourishing yin,activating blood,invigorating the spleen,benefiting water,clearing heat,moistening dryness and so on,among which the most frequently used herb was HuangQi.Based on the above results,this paper respectively constructed a network of the items of type 2 diabetes mellitus and type 2 diabetes mellitus related to the deficiency of qi and yin.We found that the top 10 of the herb network without a syndrome was HuangQi,FuLing,ShanYao,DanShen,HuangLian,GeGen,ShengDiHuang,BaiZhu,GanCao and ShanZhuYu,and the deficiency of Qi and Yin certificated of the top 10 node was HuangQi,ShanYao,ShengDiHuang,DanShen,GeGen,HuangLian,TianHuaFen,FuLing,MaiDong and GouQiZi,among which,HuangQi,ShanYao,GeGen,ShengDiHuang,FuLing,DanShen and HuangLian were the herbs that overlap each other.This suggested that the treatment of type 2 diabetes was beneficial to nourishing yin and nourishing yin,and clearing heat and activating blood circulation.We further calculated the weight of the edges,it was found that the common herbal pairs were HuangQi-ShanYao,HuangQi-GeGen,HuangQi-DanShen,and HuangQi-ShengDiHuang,while the commonly used herb pairs of the deficiency of qi-yin syndrome were HuangQi-ShanYao,HuangQi-ShengDiHuang,HuangQi-GeGen.According to the results of association rules,it was concluded that HuangQi-ShanYao,HuangQi-ShengDiHuang,HuangQi-GeGen were the 4 core herbs for the treatment of type 2 diabetes mellitus in TCM.Therefore,based on this result,this paper takes the 4 drugs as an example to the next study.2.A total of 47 active ingredients were searched for the core Chinese herbs.These components were searched by target fishing,and the targets of 4 Chinese herbs were obtained.Among them,HuangQi were 443,ShanYao were 407,ShengDiHuang were 413,GeGen were 417,and the 4 herbs have common targets.The targets of traditional Chinese medicine were matched with 333 targets related to type 2 diabetes mellitus,and in total 34 common targets were obtained.Then,we constructed a network of "Chinese herbs-ingredients-targets" and found that the different active components of 4 Chinese herbal medicines can be acted on the same targets,and the same components can be acted on different target points.We can also see from the network that the core herbs mostly from HuangQi and ShaoYao,suggesting that the two herbs act the main role in the treatment.In addition,M392 and M449 were not only the largest two nodes,but also respectively HuangQi-GeGen,ShengDi-ShanYao in the common components.This showed that HuangQi-GeGen and ShengDi-ShanYao have synergistic effect for the treatment of diseases.Then,we constructed the "protein-protein interaction network "of the 34 potential therapeutic targets of type 2 diabetes,and found that the nodes of AKT1,PPARG,INSR and IGF1 were of great contribution in the network and belong to the core targets.The biological function analysis and pathway enrichment analysis of potential targets were then made,and we found that type 2 diabetes was closely related to genetic factors,environmental factors and lifestyle,and also involves arachidonic acid secretion,fatty acid transport,positive regulation of glucose metabolism,transcription of RNA polymerase II promoter,removal of superoxide radical,placental development and other 6 major types of biological functions.In addition,it involved the regulation of a variety of disease-related pathways,such as PPAR signaling pathways,HIF-1 signaling pathways,atherosclerosis,insulin resistance,fat cytokine signaling pathways,AMPK signaling pathways,apoptotic signaling pathways,fat cell lipid solution and so on.3.47 Active components in the core Chinese herbs were butted with 4 core targets of type 2 diabetes mellitus,such as AKT1,PPAR-y,INSR and IGF1.Using the scoring value of the small molecule in the protein crystal structure as the threshold,the small molecule of the grading value of the high-altitude ligand in the molecular docking result was screened,and it was found that there were 5 small molecules larger than the original in the AKT1.The top 3 were M732,M439 and M374 in ShengDiHuang and HuangQi.For PPAR-y,13 small molecules have a good interaction with the proteins,and the top 3 were M354,M98,and M422 of HuangQi.For INSR,the scoring function of 21 compounds was higher than the original one,and the best combination with the protein was the M732 in the ShengDiHuang,the M3 74 in HuangQi and the M12297 in GeGen.For IGF1,a total of 40 small molecules were better than the original molecule,including the highest score of the M732 in the ShengDiHuang,puerarin in the M3629,and the M3 730 of the ShengDiHuang.In addition,among the top 3 of the small molecules,we found that M732 can be simultaneously acting on AKT1,IGF1 and INSR,M3 74 can simultaneously function in AKT1 and INSR.In this paper,the interaction model of target protein with 4 target proteins were analyzed by using the first two small molecule as an example.The results showed that the small molecule and target protein can produce good binding mode,it was through the hydrogen bond action,hydrophobic action,charge action interaction and so on.Conclusions1.Qi-Yin deficiency syndrome is the most common type of type 2 diabetes mellitus,HuangQi,ShanYao,ShengDiHuang and GeGen are the core Chinese herbs for the treatment of type 2 diabetes mellitus;2.The core herbs involves many key targets,such as AKT1,BMP2,IGF1,INSR,PPARA and PPARG.M392 and M449 are the main active ingredients.These herbs can participate in the treatment of the disease through multiple targets and multiple ways,which is consistent with the concept of TCM to understand human body and disease from the holistic view;3.The compounds in Chinese herbs can be combined with many kinds of protein receptors in the human body,and can cooperate with each other in the whole process from insulin production to the signal transmission of insulin,and they can directly or indirectly participate in the regulation of blood sugar,thus produce a comprehensive hypoglycemic mechanism.It confirms the theory of TCM from the micro level that HuangQi,GeGen,ShengDiHuang and ShanYao not only can supplement qi and promote body fluid,but also can invigorate the spleen and nourish yin.