|Year : 2021 | Volume
| Issue : 2 | Page : 201-208
An Exploration in the potential substance basis and mechanism of Chuanxiong Rhizoma and Angelicae Dahuricae Radix on analgesia based on network pharmacology and molecular docking
Ting-Ting Zhao1, Rui-Rui Lan1, Shang-Dong Liang2, Günther Schmalzing3, Hong-Wei Gao4, Alexei Verkhratsky5, Chuan-Hua He6, Hong Nie1
1 Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
2 Department of Physiology, Basic Medical College of Nanchang University, Nanchang, China
3 Deparment of Molecular Pharmacology, RWTH Aachen University, Aachen, Germany
4 Department of Biological Pharmaceuticals, School of Life Science, Ludong University, Yantai, China
5 Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
6 Department of Molecular Microbiology and Immunology, Brown University, Providence, USA
|Date of Submission||23-Jun-2020|
|Date of Acceptance||14-Aug-2020|
|Date of Web Publication||24-May-2021|
Prof. Hong Nie
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong
Source of Support: None, Conflict of Interest: None
Objective: The objective was to study the potential substance basis and action mechanism of Chuanxiong Rhizoma (CX) and Angelicae Dahuricae Radix (AD) on analgesia through network pharmacology and molecular docking. Materials and Methods: The active components and targets of CX and AD and pain-related genes were retrieved through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and GeneCards database. Then, the co-action targets were found, protein–protein interaction network was constructed by the String database. The Cytoscape 3.7.1 was used to construct “CX-AD-active components-pain” network. Further enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was carried out to predict its mechanism of action, the top four active components in the network were docked with the targets. Results: There are 26 compounds, 45 targets in the network. Among them, (Z)-ligustilide and beta-sitosterol, respectively, have more potential targets in CX and AD, and prostaglandin-endoperoxide synthase (PTGS2), PTGS1 have more ligands. GO analysis shows that molecular functions of CX and AD mainly performed through the G protein-coupled amine receptor activity, adrenergic receptor activity, and catecholamine binding. KEGG analysis indicates that they could exert analgesic effect on the pathways of regulating neuroactive ligand-receptor interaction, serotonergic synapse, and cGMP-PKG signaling pathway. Molecular docking results show that the active compounds are highly compatible with the structure of the protein receptor, and they interact through the hydrogen bond and π–π bond between the ligand and the active site residues. Conclusions: Through network pharmacology and molecular docking, this study preliminarily revealed the main active components, targets, and potential regulation network of CX and AD, providing a reference for the subsequent experimental research.
Keywords: Angelicae Dahuricae Radix, Chuanxiong Rhizoma, molecular docking, network pharmacology, pain
|How to cite this article:|
Zhao TT, Lan RR, Liang SD, Schmalzing G, Gao HW, Verkhratsky A, He CH, Nie H. An Exploration in the potential substance basis and mechanism of Chuanxiong Rhizoma and Angelicae Dahuricae Radix on analgesia based on network pharmacology and molecular docking. World J Tradit Chin Med 2021;7:201-8
|How to cite this URL:|
Zhao TT, Lan RR, Liang SD, Schmalzing G, Gao HW, Verkhratsky A, He CH, Nie H. An Exploration in the potential substance basis and mechanism of Chuanxiong Rhizoma and Angelicae Dahuricae Radix on analgesia based on network pharmacology and molecular docking. World J Tradit Chin Med [serial online] 2021 [cited 2021 Sep 24];7:201-8. Available from: https://www.wjtcm.net/text.asp?2021/7/2/201/316607
| Introduction|| |
With the improvement of living standards and desire for a better quality of life, demand to relieve pain caused by various diseases is increasing. Currently, common analgesics, such as nonsteroidal anti-inflammatory drugs and opioids, are effective with obvious side effects. Therefore, it is urgent to find new analgesics that are efficient, nonaddictive, and tolerable.
Herb pair is the smallest unit in the compatibility of traditional Chinese medicine (TCM) compounds, and also a common form in the clinical use of TCM. It is summarized on the basis of long-term use by medical practitioners and proved effective. Among them, Chuanxiong Rhizoma (CX) and Angelicae Dahuricae Radix (AD) are commonly used for the treatment of pain. CX is the dried rhizoma of the umbrella plant Ligusticum chuanxiong Hort. and AD is the dried radix of the umbrella plant Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f. or A. dahurica (Fisch. ex Hoffm.) Benth. et Hook. f. var. formosana (Boiss.) Shan et Yuan, respectively, which were first recorded in Shennong Bencao Jing (Shennong's Classic of Materia Medica). CX has the effect of activating blood, promoting Qi, dispelling wind, and relieving pain, which is the treatment of blood deficiency headache holy medicine. AD has the effect of releasing exterior, dispelling cold, clearing nose and orifices, eliminating dampness and tourniquet, detumescence and purulence, which is an important medicine to treat Yangming Meridian headache.
Formulas containing both CX and AD include Chuanxiong Chatiao San, Xiongzhi Shigao decoction, Chuanxiong Qingnao granules, and so on. Clinical studies have shown that the addition and subtraction of Chuanxiong Chatiao San has a good effect on migraine and angiogenic headache, which can effectively improve the clinical symptoms and improve the therapeutic effect. Chuanxiong Qingnao granule can significantly reduce headache in patients, with the characteristics of short onset time, subtle adverse reactions, and safety.
TCM has the characteristics of multiple components, multiple targets, and multiple regulation modes. Hence, the classic research methods of a single component or target are difficult to reflect the whole system of TCM. Network pharmacology was established basing on the rapid development system pharmacology, whose research ideas focus on systematization and integrity. The interaction relationship of “disease-gene-target-drug” is presented in an intuitive graph, and the intervention and influence of drugs on disease networks are systematically illustrated to better reveal the characteristics of multicomponent drug synergy and the internal mechanism of drug treatment of disease.,, Molecular docking, one of the computer-aided drug design technologies, can not only study the detailed interaction between drug molecules and their targets but also be used to find and optimize drug precursors. Through the interaction between small-molecule ligands and receptor biomacromolecules, their binding mode and affinity are predicted, and structure-based drug design is realized. It reduces the time and budget of drug development with low requirement on equipment. It is important since it has been widely used in all aspects of drug research and development.
Therefore, this study intends to predict the active components, targets, and related pathways of CX and AD, through network pharmacology and molecular docking, combined with the Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, to better clarify the mechanism of “CX-AD” on analgesia, and provide theoretical reference for further experimental research and clinical application.
| Materials and Methods|| |
Tools used were Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) (http://tcmspw.com/tcmsp.php);UniProt (https://www.uniprot.org/); GeneCards (https://www.genecards.org/); String (https://string-db.org/);Cytoscape 3.7.1; clusterProfiler; Protein data bank (PDB) (http://www.rcsb.org/); Open Babel 2.4.1; AutoDock Tools 4.2;AutoDock Vina1.1.2; R3.6.3, etc.
Screening of active components and prediction of potential targets of Chuanxiong Rhizoma and Angelicae Dahuricae Radix
Oral bioavailability (OB), which represents the speed and degree of absorption of active or active ingredients of oral drugs into systemic circulation, is one of the most important pharmacokinetic parameters in drug absorption, distribution, metabolism, and excretion. The higher the OB value is, the better the drug-likeness (DL) of the bioactive molecules is., The chemical components of CX and AD were searched by TCMSP, and the drug active ingredients were screened by combining OB ≥30% and DL ≥0.18. To increase the reliability of the predicted results, the missing active ingredients were supplemented by referring to related literature. The target proteins of the active ingredients in CX and AD were collected by using the target prediction function in the TCMSP database, and the gene names of the target proteins were obtained by using the UniProt protein database.
Screening of pain targets
By entering the “pain” keywords into the GeneCards database, the reported pain-related genes was found, and the common targets acting on the pain and active ingredients of CX and AD were screened.
Protein–protein interrelationship network construction
To retrieve the interaction relationship between the targets, the common targets were input into the String to limit the species to Homo sapiens with a minimum required interaction score to medium confidence (0.400). Then, it was further optimized with Cytoscape 3.7.1 statistical software (National Institute of General Medical Sciences of the National Institutes of Health, The United States) to obtained the protein–protein interrelationship (PPI) network.
Construction and analysis of “chuanxiong rhizoma -angelicae dahuricae radix-active ingredients-targets-pain” interaction network
According to the active ingredients, predicted targets, and pain-related targets of CX and AD, the “active ingredients-targets” interaction network was constructed using Cytoscape 3.7.1 statistical software. CytoNCA plug-in was used to analyze the nodes and find out the main active components and targets in the network.
Gene ontology molecular function and Kyoto Encyclopedia of Genes and Genomes pathway analysis
With the help of clusterProfiler database, GO molecular function enrichment analysis and KEGG pathway enrichment analysis were carried out on the common target of “CX-AD” with pain.
- Retrieved and downloaded the active ingredients, the top five compounds of degree value in the “CX-AD-active ingredients-targets-pain” interaction network, through TCMSP, and converted the active ingredients file into PDBQT format file using Open Babel 2.4.1
- Retrieved and downloaded the crystal structure of the target proteins, the top four targets of degree value in the “CX-AD-active ingredients-targets-pain” interaction network and 2 core genes in PPI network through the PDB database
- Removed the water and ligands from the target protein with AutoDock Tools 1.5.6 and add hydrogen atoms to it to calculate the charge, then exported to PDBQT file, and determined the size and center of the docking box with AutoDock Tools 1.5.6
- The active ingredients were docked with the target protein using Vina 1.1.2, and the conformation with the highest affinity was selected. The final result was analyzed and plotted with Pymol.
| Results|| |
Screening of active components and acquisition of potential targets of Chuanxiong Rhizoma and Angelicae Dahuricae Radix
In TCMSP database, the key words of CX and AD were used for the query. The results showed that there were 189 compounds related to CX, while 7 compounds meet the screening conditions and 223 compounds related to AD, while 22 compounds meet the screening conditions. To ensure the comprehensiveness and reliability of the results, the active components of CX were testified with literature review. Modern research indicates that organic acids, phthalides, alkaloids, polysaccharides, ceramides and cerebrosides are main components responsible for the bioactivities and properties of CX, among which ligustilide, ferulic acid (FER) and tetramethylpyrazine are the main active ingredients in phthalein, organic phenolic acid and alkaloid respectively. Therefore, there are 10 active ingredients in CX. Potential target proteins corresponding to active ingredients were searched through TCMSP database. The active ingredients of CX obtained a total of 40 target proteins, and the active ingredients of AD obtained a total of 44 target proteins. The predicted target protein names were converted into gene names through Uniprot database to obtain target genes. See [Table 1] and [Table 2].
Screening of pain targets and protein–protein interrelationship network
Retrieved from GeneCards database, 11,646 pain targets were obtained. A total of 2351 targets with a correlation degree >5 were selected. There are 31 potential targets of pain and CX, 33 potential targets of pain and AD, and 19 potential targets of pain and “CX-AD.” The PPI network constructed with 19 common target genes is shown in [Figure 1]. The network consists of 19 nodes and 47 edges, with an average node degree of 4.95 and an average local clustering coefficient of 0.687. The results of the PPI network show that, instead of acting independently, the drug pair of “CX-AD” had a complex interaction with the target of pain. Two core genes of MAOA and SLC6A4 may play an important role in the network.
|Figure 1: The protein–protein interaction network of the joint action targets of “Chuanxiong Rhizoma-Angelicae Dahuricae Radix” and pain. The lines represent the interaction of the proteins relationship. The size and color depth of the node represent the size of the degree value, and the line thickness and color depth represent the combined_score value|
Click here to view
”Chuanxiong rhizoma-AD-active ingredients-targets-pain” interaction network
To explain the complex network relationship between CX and AD on analgesia more clearly and intuitively, the network diagram of “CX-AD-active ingredients-targets-pain” was constructed and visualized by using the software of Cycloscape 3.7.1, as shown in [Figure 2]. CytoNCA plug-in was used to analyze and conclude that the main active components in the network were beta-sitosterol (degree: 20.0), stigmasterol (degree: 19.0), (Z)-ligustilide (degree: 17.0), FER (degree: 13.0), and myricanone (degree: 12.0); the main targets were PTGS2 (degree: 22.0), PTGS1 (degree: 10.0), ADRB2 (degree: 9.0), and SCN5A (degree: 8.0). Meanwhile, (Z)-ligustilide, FER, and mandenol are contained in both CX and AD. These compounds with multiple targets may play a relatively important role in the analgesic effects of CX and AD. In addition, 20 of the 45 potential targets are linked to two or more compounds, indicating that the same target can also be regulated by multiple compounds simultaneously. This network reflects the complex network of multicomponent and multitarget interactions of TCM and verifies that the pain treatment by CX and AD are performed through multiapproaches, multilinks, multitargets, and overall coordination.
|Figure 2: “Chuanxiong Rhizoma-Angelicae Dahuricae Radix-active ingredients-targets-pain” interaction network. The green rectangle nodes represent Chuanxiong Rhizoma and Angelicae Dahuricae Radix; the blue triangle nodes represent the active ingredients of Chuanxiong Rhizomaand AD; The orange circular nodes represent the target of joint action between Chuanxiong Rhizoma, Angelicae Dahuricae Radix, and pain; the pink rhomboid node represents pain; the sky-blue triangle represents the core active components; the red circle represents the core target proteins; the lines represent the nodes of the interaction relationship|
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Gene ontology functional enrichment analysis
With the help of Perl and R programming, GO function enrichment analysis was carried out on the target, and the threshold value was set as P < 0.05. Through analysis, it was found that the target genes of “CX-AD” are mainly concentrated in 55 kinds of molecular functions. [Figure 3] lists the top 20 with high significance. The molecular functions are mainly concentrated in the G protein-coupled amine receptor activity, adrenergic receptor activity, catecholamine binding, steroid hormone receptor activity, steroid binding, sodium ion transmembrane transporter activity, and other related functions.
|Figure 3: Gene ontology molecular function analysis of the targets of ”CX-AD” and pain. The length and color are determined by the number of associated genes and their P values|
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KEGG pathway analysis
A total of 22 signaling pathways were obtained by KEGG analysis, and the top 20 pathways of higher significance are listed in [Figure 4]. According to the analysis in [Figure 4], the analgesic mechanism of “CX-AD” mainly involves the neuroactive ligand-receptor interaction, serotonergic synapse, cGMP-PKG signaling pathway, adrenergic signaling in cardiomyocytes, calcium signaling pathway, and other related pathways. The related genes include ADRA1B, ADRA1A, ADRA2A, ADRB1, ADRB2, CHRM2, MAOA, MAOB, PTGS1, PTGS2, SCN5A, and SLC6A4.
|Figure 4: Kyoto Encyclopedia of Genes and Genomes pathway analysis of the targets of “CX-AD” and pain. The size and color of the dots are determined by the number of associated genes and their P values|
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[Table 3] shows the potential binding of the main active components to the main proteins. The three-dimensional structure of these compounds is highly compatible with the structure of the protein receptor, and they interact through hydrogen bonds and π–π bonds between the ligand and the active site residues. These small molecules bind to amino acid residues such as histidine, phenylalanine, leucine, and tryptophan. The best docking ligand of PTGS2, ADRB2, and SLC6A4 is stigmasterol, and the best docking ligand of PTGS21, SCN5A, and MAOA is beta-sitosterol. The highest score of docking protein is stigmasterol, which binds to amino acids such as HIS93, PHE194, HIS296, TYR308, and ASN312 through hydrogen bonds and π–π bonds. The binding pattern of active component stigmasterol with ADRB2 is shown in [Figure 5].
|Table 3: Affinity and amino acid sites of ligand.protein detected by molecular docking|
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| Discussion|| |
Modern pharmacological studies have shown that the analgesic pathways of CX and AD mainly include reducing the secretion of enkephalin and nitric oxide, increasing the content of β-endorphin and 5-hydroxytryptamine (5-HT), and decreasing the expression of C-FOS, cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2).,, In this study, we found the active components, targets, and pathways of CX and AD through the network pharmacology. Meanwhile, molecular docking was used to verify the binding of the compounds to the target proteins.
Among them, PTGS, also known as COX, is divided into PTGS1 and PTGS2, which is a key enzyme in the initial step of PG synthesis. PG is an important mediator of an inflammatory response, which can cause pain and edema of erythema vasodilatation in the inflammatory site. The increase of PGE2 can directly cause pain or increase the sensitivity of nerve roots to bradykinin and other pain-causing substances to reduce the threshold of nerve pain and trigger pain. Studies have shown that (Z)-ligustilide and tetramethylpyrazine can inhibit the expression of COX-2.,, The 5-HT reduction will lead to a decrease in the pain threshold within the thalamencephalon. Studies have shown that the compatibility of 4:3 in CX-Gastrodia elata could have better efficacy for treating migraine through upregulating 5-HT levels. Senkyunolide, an active component of CX, is traditionally used to treat migraines. The mechanism of pain relief in migraine model rats may be through adjusting the levels of monoamine neurotransmitters and their turnover rates.
These results indicate the reliability of predicted targets, and providing a basis for further elucidating the analgesic mechanism of “CX-AD”. However, there are few studies on the active components, such as beta-sitosterol, stigmasterol, and myricanone and the targets such as ADRB2 and SCN5A. The above active ingredients, targets, and other pathways with more enrichment, such as neuroactive ligand-receptor interaction, cGMP-PKG signaling pathway, and calcium signaling pathway, may play a key role in the analgesic effect of “CX-AD” and deserve further study.
To sum up, studies have shown that “CX-AD” has a variety of active ingredients, targets, signal pathways, and biological processes, which provided a possible explanation on the material basis of “treating different diseases with the same treatment” and “treating the same diseases with different treatment.” It reflects the functional characteristics of “multi-components-multi-targets-multi-pathways” in TCM, providing a research basis on the specific mechanism of “CX-AD” in analgesia. However, there are some limitations of network pharmacology and molecular docking. The results may be deviated from the experimental results, and further clinical and experimental studies were needed to provide a more effective scientific basis on promoting research and development of new drugs.
| Conclusions|| |
Through network pharmacology and molecular docking, this study preliminarily revealed the main active components, targets, and potential regulation network of CX and AD, providing a reference for the subsequent experimental research.
This work was financially supported by NSFC-DFG (No. 81861138042), Natural Science Foundation of China (No. 81673634), Natural Science Foundation of Shandong, China (No. ZR2019MC004), and the high-end talent team construction foundation (No. 108-10000318).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]