Investigating the pharmaceutical substances and action mechanisms of Changmaxifeng granules against tic disorders

Abstract

Background: Tic disorders (TDs) are a type of neurological and psychiatric disorder characterized by vocal or motor tics in the head, body, or limbs. Clinical studies have shown that Changmaxifeng granules (CG) can treat TDs. However, the pharmaceutical substances and mechanism of action of CG remain unclear.

Aim: To investigate the pharmaceutical substances and action mechanisms of CG against TDs, this study employs serum medicinal chemistry, network pharmacology, and molecular docking analysis.

Methods: Ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry was used to identify the blood-absorbed constituents of CG; Network pharmacology was then used to integrate these compounds with disease targets, followed by protein-protein interaction (PPI) networks analysis to pinpoint key proteins. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses combined with molecular docking elucidated the underlying mechanism of action.

Results: Overall, 187 chemical components, including terpenoids, sugars, phenolic acids, and flavonoids, were identified in vitro. In addition, 75 components, namely 49 prototype components and 26 metabolites, were identified in vivo. The PPI results revealed 225 overlapping targets, with TNF, IL-6, FOS, VEGFA, and ESR1 being the major targets. GO and KEGG analyses were performed to identify key signaling pathways and biological processes. Paeonol, evofolin B, aspalathin, and paeoniflorin were identified as potential pharmacodynamic substances based on the results of the "compound-target" network. The maximum binding energy between the core target and the active ingredient was less than -4.7 kcal/mol, indicating that the pharmacophore exhibited a strong affinity toward the core ingredient.

Conclusion: This study elucidated the in vitro and in vivo chemical components of CG and outlined their potential targets and action mechanisms. This study provides a basis for further research into the action mechanism and clinical application of CG.

Keywords: Against tic disorders; Changmaxifeng granule; Chemical components; Molecular docking; Network pharmacology.

Figure 1

The results of in vitro chemical composition analysis. A: Total ion current diagram of negative ion mode; B: Total ion current diagram of positive ion mode; C: Total ion current diagram of reference in negative ion mode; D: Class of chemical composition of Changmaxifeng granules (CG); E: Source of chemical composition of CG. C1 for gallic acid; C2 for gastrodin; C3 for albiflorin; C4 for paeoniflorin; C5 for 1,2,3,4,6-pentagalloylglucose; C6 for 3, 6′-disinapoyl sucrose.

Figure 2

Possible cleavage pattern and secondary mass diagram. A: The degradation pattern and secondary mass diagram of paeoniflorin; B: The degradation pattern and secondary mass diagram of onjisaponin Y; C: The degradation pattern and secondary mass diagram of 3,6’-disinapoyl sucrose; D: The degradation pattern and secondary mass diagram of tenuifoliside A; E: The degradation pattern and secondary mass diagram of parishin B; F: The degradation pattern and secondary mass diagram of gallic acid; G: The degradation pattern and secondary mass diagram of polygalaxanthone VIII; H: The degradation pattern and secondary mass diagram of acetyl glutamic acid.

Figure 3

Characterization results of plasma components. A: Plasma total ion current diagram of negative ion mode; B: Plasma total ion current diagram of positive ion mode.

Figure 4

Structural formulas of the blood-entry prototype components. A: Structural formulas of the blood-entry prototype components from Baishao; B: Structural formulas of the blood-entry prototype components from Tianma; C: Structural formulas of the blood-entry prototype components from Shichangpu; D: Structural formulas of the blood-entry prototype components from Yuanzhi. Gal: Galactose; Api: Apiofuranosyl; Rha: Rhamnose; Ara: Arabinose; Xyl: Xylose; TC: 3,4,5-trimethoxy cinnamoyl; DC: 3,4-dimethoxy cinnamoyl.

Figure 5

Possible metabolic pathways of the components that enter the bloodstream. A: The metabolic pathways of 23-hydroxybetulinic acid; B: The metabolic pathways of gastrodin; C: The metabolic pathways of paeoniflorin; D: The metabolic pathways of gallic acid; E: The metabolic pathways of onjisaponin F, 3',6-disinapoylsucrose and sibiricose A5.

Figure 6

The results of network pharmacology. A: The Venn diagram of the intersecting targets; B: The protein interaction network diagram; C: Top 10 of protein interaction network diagram; D: The Gene Ontology enrichment results; E: The Kyoto Encyclopedia of Genes and Genomes enrichment results; F: The component-target-pathway-disease topological network. TD: Tic disorder; CG: Changmaxifeng granules.

Figure 7

The results of molecular docking. A: Results of molecular docking; B: The binding mode of VEGFA with peoniflorin; C: The binding mode of AKT1 with evofolin, and the binding mode of VEGFA with peoniflorin; D: The binding mode of ESR1 with peoniflorin; E: The binding mode of FOS with tenuifolin; F: The binding mode of IL-6 with tenuifolin.