Chemoinformatics-based Screening And Mechanism Investigation Of Heart Failure Related Drugs

Heart failure is a common,expensive,potentially fatal disease.In recent years,the prevalence and morbidity of heart failure are increasing year by year.Heart failure has developed into a common public problem.In this paper,we used chemoinformatics tools combined with bioassay validations to identify small molecular antagonists targeting tumor necrosis factor-?.In addition,the integration of chemoinformatics tools and network pharmacology concept were used to explore the potential mechanism of sini decoction against heart failure.And a herbal medicine network pharmacology platform for heart failure was built up based on above two methods,for target identification and mechanism investigation of anti-heart failure traditional Chinese medicine formulas,herbs and compounds.1.Discovery of Novel Ligands for TNF-? through Structure-Based Virtual Screening and Biological AssayTumor Necrosis Factor alpha(TNF-?)is a presently potential target for heart failure.Limited numbers of TNF-? chemical inhibitors have been reported,making the identification of small molecule alternatives in urgent need.Recent studies mainly focused on identifying small molecules that directly bind to TNF-? or TNF receptor-1(TNFR1),and/or inhibit the interaction between TNF-? and TNFR1,and regulate related signaling pathways.In this study,we presented in silico methods combined with bioassay validations to identify novel TNF-? binding antagonists.Pharmacophore model and molecular docking were applied to identify potential TNF-? antagonist.We obtained 10 virtual hits and subjected them to surface plasmon resonance(SPR)based assays,resulting four ligands of different scaffolds binding with TNF-?.T1,as the most active compound with respective Kd values of 11 ?M for TNF-?,showed similar activity to those of known antagonists.Further cell-based assay also demonstrated the similar activity of T1 as compared to known antagonist C87.Our work not only produces several TNF-? antagonists with novel scaffolds for further structural optimization,but also demonstrates the power of our in silico methods for TNF-? based drug discovery.2.Investigation of the Therapeutic Effectiveness of Active Components in Sini Decoction by a Comprehensive GC/LC-MS based Metabolomics and Network Pharmacology ApproachesAs a classical formula,Sini decoction(SND)has been fully proved to be clinically effective in treating doxorubicin(DOX)-induced cardiomyopathy.Current chemomics and pharmacology proved that the total alkaloids(TA),total gingerols(TG),total flavones and total saponins(TFS)are the major active ingredients of Aconitum carmichaelii,Zingiber officinale and Glycyrrhiza uralensis in SND respectively.Our animal experiments in this study demonstrated that the above active ingredients(TAGFS)were more effective than formulas formed by any one or two of the three individual components and nearly the same as SND.However,very little is known about the action mechanisms of TAGFS.Thus,this study aimed to use for the first time the combination of GC/LC-MS based metabolomics and network pharmacology for solving this problem.By metabolomics,it was found that TAGFS worked by regulating six primary pathways.Then,network pharmacology was applied to search for specific targets.17 potential cardiovascular related targets were found through molecular docking,11 of which were identified by references,which demonstrated the therapeutic effectiveness of TAGFS using network pharmacology.Among these targets,four targets,including phosphoinositide 3-kinase gamma,insulin receptor,ornithine aminotransferase and glucokinase,were involved in the TAGFS regulated pathways.Moreover,phosphoinositide 3-kinase gamma,insulin receptor and glucokinase were proved to be targets of active components in SND.In addition,our data indicated TA as the principal ingredient in the SND formula,whereas TG and TFS served as adjuvant ingredients.We therefore suggest that dissecting the mode of action of clinically effective formulae with the combination use of metabolomics and network pharmacology may be a good strategy.3.Drug Target Identification Using Network Analysis: Taking Active Components in Sini Decoction as an ExampleIdentifying the molecular targets for the beneficial effects of active small-molecule compounds simultaneously is an important and currently unmet challenge.In this study,we firstly proposed network analysis by integrating data from network pharmacology and metabolomics to identify targets of active components in sini decoction(SND)simultaneously against heart failure.To begin with,48 potential active components in SND against heart failure were predicted by serum pharmacochemistry,text mining and similarity match.Then,we employed network pharmacology including text mining and molecular docking to identify the potential targets of these components.The key enriched processes,pathways and related diseases of these target proteins were analyzed by STRING database.At last,network analysis was conducted to identify most possible targets of components in SND.Among the 25 targets predicted by network analysis,TNF-? was firstly experimentally validated in molecular and cellular level.Results indicated that hypaconitine,mesaconitine,higenamine and quercetin in SND can directly bind to TNF-?,reduce the TNF-?-mediated cytotoxicity on L929 cells and exert anti-myocardial cell apoptosis effects.We envisage that network analysis will also be useful in target identification of a bioactive compound.4.HF-NetPharm: An Herbal Medicine Network Pharmacology Platform for Heart FailureHerbal formulas as multi-target therapy representatives have successfully helped ancient and contemporary people in dealing with different kinds of diseases,such as heart failure,for thousands of years.However,their molecular mechanisms are difficult to be clarified with the lack of appropriate approaches.Herein,an herbal medicine network pharmacology platform for heart failure(HF-NetPharm,www.cbligand.org/HF)was constructed to facilitate the mechanisms-of-action study of herbal formulas.This platform contains information of 46 herbal formulas,which consists of 111 medicinal herbs and 14,111 ingredients isolated from these herbs,with anti-heart failure therapeutic effect.It also assembled literature reported heart failure related chemogenomics data,containing 259 target proteins associated with heart failure and 77 drugs approved or in clinical trials for the treatment of heart failure.To help drug target identification,powerful computational tools,such as our established Target Hunter and HTDocking,were also integrated.Furthermore,we have presented the application of HF-NetPharm in three cases for target prediction of active small molecules,polypharmacology analysis of FDA-approved drugs and herbal ingredients,and network pharmacology analysis of an herbal formula with anti-heart failure effect.The predictions were validated by literature reported data and our in vitro experiments.Overall,HF-NetPharm will enrich our knowledge in natural products-based drug discovery,heart failure-related target identification,polypharmacology research and network pharmacology study of herbal formulas.