Tougu Xiaotong Capsules For Treating Arthritis According To The Principle Of “Same Treatment For Different Diseases”: Analysis Based On Integrated Pharmacology, Molecular Docking Techniques And Molecular Dynamics Simulation

Abstract

BACKGROUND: Our previous research found that Tougu Xiaotong Capsules can be used not only for the treatment of osteoarthritis, but also for rheumatoid arthritis and gouty arthritis. However, the specific mechanism of action of "Same Treatment for Different Diseases" is still unclear.

OBJECTIVE: To identify the main effects and mechanisms of Tougu Xiaotong Capsules in the treatment of osteoarthritis, rheumatoid arthritis and gouty arthritis with the treating principle of "Same Treatment for Different Diseases" by the methodologies of network pharmacology, molecular docking and molecular dynamics simulations. METHODS: The active chemical components of Tougu Xiaotong Capsules and their corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Swiss Target Prediction database. The disease genes for osteoarthritis, rheumatoid arthritis and gouty arthritis were obtained from the GeneCards and OMIM databases. Cytoscape 3.7.2 software was used to construct a drug-componentdisease-target network diagram and a protein-protein interaction network. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were conducted using the Daivd database. Molecular docking simulations were performed on the CB-DOCK2 website, and molecular dynamics simulations were carried out using the GROMACS 2020.6 software. RESULTS AND CONCLUSION: (1) A total of 50 active components of Tougu Xiaotong Capsules were screened, with 184 potential targets and 29 intersection targets with the three types of arthritis. (2) The gene ontology enrichment analysis of the intersection targets indicated that the key gene functions of Tougu Xiaotong Capsules in treating the three types of arthritis were found to be cellular response to lipopolysaccharide, inflammatory response, extracellular matrix, protein binding, zinc ion binding, etc. (3) Kyoto Encyclopedia of Genes and Genomes enrichment analysis identified key pathways as interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, NOD-like receptor and Toll-like receptor signaling pathways. (4) Six core targets [interleukin-6, interleukin1B, prostaglandin endoperoxide synthase 1, prostaglandin endoperoxide synthase 2, cytochrome P450 1A2 (CYP1A2) and C-X-C chemokine ligand 8] were determined based on the protein-protein interaction network. (5) Molecular docking results confirmed that (+)-catechin, β-sitosterol, kaempferol, myricetin, and wallichilide had good structure-activity relationships. Molecular dynamics simulations further confirmed the stable binding of CYP1A2 with wallichilide, corroborating the network pharmacology and molecular docking results. Therefore, Tougu Xiaotong Capsules may regulate the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and other signaling pathways by targeting interleukin-1B, prostaglandin endoperoxide synthase 1, prostaglandin-endoperoxide synthase 2 and CYP1A2, exert an effect of "Same Treatment for Different Diseases" on osteoarthritis, rheumatoid arthritis and gouty arthritis.

CCISTANCHE HERBAL SUPPLEMENTS FOR OSTEOARTHRITIS

Keywords: Tougu Xiaotong Capsules; same treatment for different diseases; osteoarthritis; rheumatoid arthritis; gouty arthritis; integrated pharmacology; molecular docking technology; molecular dynamics simulation; engineered tissue construction

Introduction

Osteoarthritis is a primary or secondary disease of bones or joints with complex etiologies. The prevalence of several common osteoarthritis, rheumatoid arthritis, and gouty arthritis is increasing year by year, becoming a serious public health problem that affects the quality of life of patients [1-3]. Traditional Chinese medicine believes that osteoarthritis is caused by kidney deficiency, liver qi stagnation, and invasion of dampness. The liver governs the tendons and the kidney governs the bones. The decline of liver and kidney function affects the nourishment and repair ability of tendons and bones; the invasion of dampness aggravates the swelling and pain of joints, which often occur in the knee and ankle joints of the lower limbs. The principle of treating osteoarthritis is mainly to nourish the kidney and soften the liver, activate blood circulation and dispel wind, and dispel dampness and relieve pain.

In traditional Chinese medicine, rheumatoid arthritis is considered to be a disease caused by "exogenous pathogenic factors due to deficiency of positive energy in the body", that is, a disease caused by the invasion of external pathogens due to the weakness of positive energy in the body. Zheng deficiency refers to the imbalance of qi and blood, yin and yang in the human body, while exogenous pathogens such as wind, cold, and dampness invade the meridians, resulting in poor circulation of qi and blood, causing symptoms such as joint swelling, pain, and stiffness, which mainly affect the small joints of the hands and feet, especially the joints of the fingers and toes, and often manifest as symmetrical lesions. The principle of treating rheumatoid arthritis is to strengthen the body and eliminate evil, strengthen the body, and relieve joint inflammation. Gouty arthritis is believed to be related to liver and kidney dysfunction in traditional Chinese medicine. The liver is responsible for regulating qi and qi, and stagnation of liver qi can lead to uric acid metabolism disorders; the kidney is responsible for water metabolism, and insufficient kidney qi can affect the excretion of uric acid, which mainly affects large joints such as ankle joints, knee joints, and wrist joints, especially nocturnal attacks are more common. The principle of treating gouty arthritis is to clear away heat and dampness, activate blood circulation and remove blood stasis, and harmonize the liver and kidney. The above diseases all occur in the joints of the limbs, and the clinical manifestations are mainly pain. In severe cases, deformities and functional disorders may occur.
All three can be seen in the category of "arthralgia" in traditional Chinese medicine, and can be summarized as the syndrome of deficiency of vital energy and exogenous wind, cold and dampness.

Tonggu Xiaotong Capsule is an in-hospital preparation of the Second People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine (approval number: Minyao Preparation Z20190010000), which is made of Morinda officinalis, white peony root, Chuanxiong and Radix Achyranthis Bidentatae. The research team's previous studies found that Tonggu Xiaotong Capsule can delay cartilage degeneration and relieve pain in the treatment of osteoarthritis through multiple links, multiple levels and multiple targets [4-7].

Long-term clinical practice has found that Tougu Xiaotong Capsules also have good therapeutic effects on rheumatoid arthritis and gouty arthritis. In order to further promote the clinical application and secondary development of Tougu Xiaotong Capsules and clarify its regulatory mechanism, this study used the strategy of integrative pharmacology to explore the potential pharmacological substances and mechanisms of action of Tougu Xiaotong Capsules in treating osteoarthritis, rheumatoid arthritis and gouty arthritis [8-9]; molecular docking technology was used to preliminarily verify the interaction between potential active ingredients and key targets, and potential active ingredients and targets were screened; combined with molecular dynamics simulation to observe the stable binding state of ingredients and targets, and further verify the results of molecular docking, thereby comprehensively exploring the mechanism of action of Tougu Xiaotong Capsules in treating osteoarthritis, rheumatoid arthritis and gouty arthritis, providing more scientific basis for the clinical application of Tougu Xiaotong Capsules.

2 Results

2.1 Active ingredients and predicted targets

Through the TCMSP database search, screening was performed according to the criteria of OB > 30% and DL > 0.2, and duplicates were removed to obtain 50 active ingredients in Tougu Xiaotong Capsules, including 20 from Morinda officinalis, 13 from Paeonia lactiflora, 7 from Ligusticum chuanxiong, and 10 from Radix Achyranthis Bidentatae. Using TCMSP and Swiss Target Prediction to predict the targets of active ingredients, a total of 184 potential targets were obtained, and the top 10 active ingredients are shown in Table 1.

Table 1 ｜ Active ingredients of Tougu Xiaotong Capsules (top 10 oral bioavailability values)