Integrated Pharmacology and Network Pharmacology of the Active Components of Xinjiang Zukamu Granules to Prevent and Cure novel coronavirus Pneumonia
Novel coronavirus disease in 2019 (COVID-19) is an acute lung infection caused by enveloped RNA virus. The novel coronavirus (formerly known as 2019 nCoV, now known as SARS CoV-2) mainly invades the respiratory system, mainly showing fever, dry cough and fatigue. Severe cases can rapidly progress to acute respiratory distress syndrome (SARI), septic shock, and even multiple organ failure. It also shares significant similarities with a group of SARS like coronaviruses in terms of pathogenic mechanisms and clinical manifestations. SARS-CoV-2 can bind to angiotensin converting enzyme 2 (ACE2) and enter cells, causing infection. After SARS-CoV-2 enters the host cell, it releases RNA and aggregates with ribosomes in the cell, translating the small ribonucleic acid virus’s 3C protease (3CLpro). Therefore, 3CLpro and ACE2 also play a crucial role in the pathogenesis of SARS-CoV-2. However, there is still a lack of effective clinical drugs to suppress the virus.

According to the recommendation of the Expert Consensus on Traditional Chinese Medicine (Uygur Medicine) Treatment of Pneumonia Infected with novel coronavirus released by the Health Commission of Xinjiang Uygur Autonomous Region on February 1, many local medicines in Xinjiang are on the list. For patients with damp and hot blood stasis, it is recommended to use Zukamu granules (ZKMG) as appropriate. ZKMG is composed of 10 traditional Chinese medicines, including Shan Nai, Sleep Lotus, Peppermint, Jujube, Chamomile, Po Bu Mu Guo, Licorice, Shu Kui Zi, Rhubarb, and Poppy Shell, which have good anti influenza virus, antibacterial, and anti-inflammatory effects.

The integrated pharmacology based research platform of traditional Chinese medicine (TCMIP) V2.0 uses the online database of the Encyclopedia of Traditional Chinese Medicine (ETCM) as its data resource, including seven functional modules: disease-related molecular sets and their functional mining, syndrome related molecular mining and functional analysis, traditional Chinese medicine drug properties related molecular mining and functional analysis, target prediction and functional analysis of traditional Chinese medicine (including prescriptions), analysis of prescription and medication rules, mining of traditional Chinese medicine association networks, and reverse search of traditional Chinese medicine (including prescriptions). Network pharmacology is an emerging discipline that combines systems biology, computer biology, and multidisciplinary pharmacology. The interaction mechanism between drugs and diseases can be explored from the perspective of multi-level network stability. This study utilizes traditional Chinese medicine integrated pharmacology, network pharmacology, and molecular docking to comprehensively analyze the active ingredients of Zukamu granules. Molecular docking technology is used to dock the active ingredients of ZKMG with 3CLpro and ACE2, exploring the material basis of ZKMG’s effect on COVID-19 and providing certain reference and basis for its clinical application.

TCMIP V2.0 is beneficial for overcoming the “fragmentation” phenomenon between “chemical composition in vivo processes pharmacological activity symptomatic effects” in modern research of traditional Chinese medicine, and forming a pharmacological evaluation system and research method with Chinese medicine characteristics. This article found through the integration of traditional Chinese medicine pharmacology platform and network pharmacology that the optimal binding energies of 16 active ingredients of ZKMG with 2019 nCoV Mpro and ACE2 are lower than those of clinically recommended chemical drugs. According to the MACCS molecular fingerprint feature extraction method and the Tanimoto coefficient defined similarity measurement method, 16 active ingredients were scored for similarity with FDA marketed drugs. The results showed that among them, 10 active ingredients, including luteolin, coumarin, rhein, mangiferin, kaempferol, half licorice isoflavone B, isorhamnetin, cilantrol, kaempferol, and quercetin, met the requirement of score ≥ 0.8. Luteolin inhibits sepsis induced acute lung injury through its anti-inflammatory and antioxidant activities. Rhein effectively improves pulmonary inflammation and edema in rats with acute lung injury induced by oleic acid by improving the microvascular barrier in the lungs. Formononetin induces apoptosis and inhibits the growth of lung cancer cell line A549. Kaempferide enhances the chemotherapy sensitivity of human lung adenocarcinoma A549 cells by reducing the expression of Akt and claudin-2. Diosmetin has a certain therapeutic effect on meconium induced acute lung injury in neonatal rats by reducing arterial oxygenation index and inflammatory factor expression levels. Patients infected with SARS-CoV-2 virus have a large amount of IFN – γ, MCP-1, IP-10, and IL-I β. SARS-CoV-2 virus infection leads to increased secretion of IL-4 and IL-10, which suppress inflammation. Quercetin exerts anti-inflammatory effects by downregulating IL-6, IL-1 β, and TNF, as well as upregulating IL-10. Kaempferol has a protective effect on virus induced acute lung injury in mice by reducing oxidative stress and significantly lowering inflammatory factors such as TNF – α, IL-6, and IL-1 β in bronchoalveolar lavage fluid, inhibiting the NF – κ B signaling pathway. The above provides evidence for the prediction results of the active ingredients in Xinjiang Zukamu granules for the prevention and treatment of COVID-19. There are relatively few research reports on the components such as eriodictyol, semi licorice isoflavone B, and isorhamnetin, and further research is needed.

The multidimensional network analysis of traditional Chinese medicine active ingredients core targets key pathways shows that there is an active ingredient in ZKMG that interacts with multiple core targets, and there is also a phenomenon of different active ingredients being used for the same core target. This reflects the mechanism of the joint action between multiple components and targets in traditional Chinese medicine. KEGG pathway analysis revealed that core targets such as PIK3CG, AKT1, and CDK6 simultaneously participate in signaling pathways related to the nervous system, endocrine system, and immune response, as well as small cell lung cancer and non-small cell lung cancer, which are the most relevant to the lungs.

In summary, 10 active ingredients, including luteolin, coumarin, rhein, mangiferin, kaempferol, half licorice isoflavone B, isorhamnetin, cilantrol, kaempferol, and quercetin, may exert therapeutic effects through synergistic action with 3C like proteases on multiple targets and pathways, thereby playing an auxiliary role in the treatment of COVID-19. Given the limitations of integrating pharmacology and molecular docking, experimental research is needed to provide theoretical and experimental basis for ZKMG treatment of COVID-19 and later drug development.