Chemogenomics Knowledgebase and Targethunter forudPolypharmacology Analysis of A Traditional Chinese Herbal Formula, 'Sini Decoction'

摘要

To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) often prescribe a combination of multiple herbs, called Traditional Chinese Herbal formulae (TCHF), according to the compatibility principle of TCM. To clarify the possible compatibility mechanism of formulae with systems polypharmacology analyses, we use Sini Decoction (SNT), which has been proven to be effective in treating cardiovascular diseases (CVD), as a model. The main components of SND are Aconitum carmichaeli Debeaux [Ranunculaceae], Zingiber officinale Roscoe [Zingiberaceae] and Glycyrrhiza uralensis Fisch. ex DC [Febaceae]. In this research, we initially construct a chemical library with 347 reported constituents in SND, and narrowed the library to 40 compounds by selecting representative chemical structures. Then, we constructed several databases for the specific indications of SND, including heart failure, myocardial infarction, and shock, and an integrated database for CVD to perform high throughput docking with the 40 compounds in SND. Systems pharmacology is applied to investigate the polypharmacological mechanisms of SND formulae in treatment of CVD. The predicted results showed that 31 ingredients in SND were associated with 33 targets related to the autonomic nervous system, the renin-angiotensin aldosterone system, blood coagulation, ionic channels and the glucocorticoid receptor. Through analysis of the compound-target interaction, we found multiple active chemical ingredients might interact with the same target, thus explaining the synergistic mechanisms of SND as ‘‘Jun (emperor) - Chen (minister) - Zuo (adjuvant) - Shi (courier)’’. To validate the polypharmacological effects predicted by molecular docking, the experimental validation was further performed on three selected representative constituents (aconitine, liquiritin, and 6-gingerol) according to our predicted results. The results showed that the three constituents combination could produce the same cardiac effects in the rat heart failure model with the combination of three herbs in SND, and confirmed the three constituents we predicted are most likely the active constituents. This computational systems pharmacology data revealed that aconitine was the principal component of the formula, whereas liquiritin and 6-gingerol served as adjuvant ingredients, as 6-gingerol can enhance the cardiac effects of aconitine, and liquiritin can alleviate the arrhythmia caused by aconitine. The predictions are all congruent with the other reports and experiments results.