| Chuanwu is the dried root of Aconitum carmichaelii DEBX.In modern clinical application,Chuanwu is effective in treating rheumatoid arthritis.Pharmacological studies show that Radix Aconiti has many pharmacological activities,such as analgesic,anti-inflammatory,anti rheumatic,immunomodulatory and so on;at the same time,Radix Aconiti has strong cardiotoxicity and neurotoxicity.There are many reports about poisoning and even death of Aconitum carmichaeli,which leads to less clinical application of Aconitum carmichaeli.In this paper,network pharmacology,molecular docking technology and structure toxicity relationship analysis were used to analyze the main active/toxic components,key targets and mechanism of action of Aconitum carmichaeli from the perspective of efficacy and toxicity,so as to provide theoretical basis for the clinical safe application of Aconitum carmichaeli and lay the foundation for further development and research.Research methods:1.Based on network pharmacology,the targets of pharmacodynamics(analgesia,anti rheumatism)and toxicity(arrhythmia,central nervous system)of Radix Aconiti carmichaeli were predicted,and the key targets and signaling pathways were screened by PPI,go and KEGG enrichment analysis.2.Based on molecular docking technology and structure toxicity relationship analysis,the interaction mode and intensity between components and proteins of Aconitum carmichaeli were explored to screen active/toxic components.The results are as follows:1.The results of David database analysis showed that the components of Aconitum carmichaeli had analgesic effect through cholinergic synapse,serotonergic synapse and dopaminergic synapse;Through vascular endothelial growth factor signaling pathway,the regulation of inflammatory mediators on TRP channel,toll like receptor signaling pathway,leukocyte trans endothelial migration,B cell receptor signaling pathway,T cell receptor signaling pathway,tumor necrosis factor signaling pathway,PI3K-Akt signaling pathway,the anti rheumatic effect is exerted;Arrhythmia toxicity is induced by calcium signaling pathway and adrenergic signal transduction in cardiomyocytes;Central neurotoxicity is produced through Parkinson’s disease signaling pathway.The annotation analysis of signal pathway in KEGG database showed that CHRM2,HTR1 A and DRD2 were the key targets of analgesia and central nervous system;PIK3CA and MAPK3 are the key targets of anti rheumatism;ADRB2 and CHRM1 are the key targets of arrhythmia.2.The docking results showed that the binding energies of all the components except uracil were less than-5 kcal / mol,indicating that the ligand molecules could spontaneously bind to the receptor protein.In addition to the comparison of binding energy,the hydrogen bond formation between the components of Radix Aconiti and the key targets was examined.The results showed that C-19 diterpenoid alkaloids,higenamine,Songorine and aurantiamide were found Acetate has high affinity and intrinsic pharmacological activity;through the analysis of structure toxicity relationship,it is considered that the interaction relationship between C-19 diterpenoid alkaloids and key targets in Aconitum carmichaeli is basically consistent with the active group position of C-19 diterpenoid alkaloids in previous literature,among which c14-OCOC6H5,c8-OCOCH3,c3-OH and c10-OH make greater contribution to cardiotoxicity.Therefore,in the C-19 diterpenoid alkaloids,diester alkaloids are the main toxic components of Aconitum carmichaeli.After c8-OCOCH3 was removed to form monoester alkaloid,its cardiotoxicity decreased,but its therapeutic index increased.Conclusion: Aconitine,mesaconitine,hypaconitine,beiwutine and higenamine were the main toxic components of Radix Aconiti,which produced arrhythmic toxicity mainly through adrenergic receptor-mediated calcium signaling pathway and myocardial cell adrenergic signaling pathway;benzoylmesaconitine,Songorine and aurantiamide were the main effective components of Radix Aconiti Acetate,mainly through cholinergic synapse,5-hydroxytryptamine synapse and dopamine synapse,produces central /peripheral analgesic effect;through PI3K-Akt and MAPK signaling pathway,multiple anti-inflammatory pathways participate in the way to play the role of anti rheumatism. |
