key: cord-1052986-sa31x6es authors: Lin, Haixiong; Wang, Xiaotong; Liu, Minyi; Huang, Minling; Shen, Zhen; Feng, Junjie; Yang, Huijun; Li, Zige; Gao, Junyan; Ye, Xiaopeng title: Exploring the treatment of COVID‐19 with Yinqiao powder based on network pharmacology date: 2021-01-15 journal: Phytother Res DOI: 10.1002/ptr.7012 sha: 783c10ba71133c56be1fd6fcd10f6540bee3fa5b doc_id: 1052986 cord_uid: sa31x6es Coronavirus disease 2019 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). In China, Yinqiao powder is widely used to prevent and treat COVID‐19 patients with Weifen syndrome. In this study, the screening and verification of active ingredients, target selection and DisGeNET scoring, drug–ingredient–gene network construction, protein–protein interaction network construction, molecular docking and surface plasmon resonance (SPR) analysis, gene ontology (GO) functional analysis, gene tissue analysis, and kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were used to explore the active ingredients, targets, and potential mechanisms of Yinqiao powder in the treatment of COVID‐19. We also predicted the therapeutic effect of Yinqiao powder using TCM anti‐COVID‐19 (TCMATCOV). Yinqiao powder has a certain therapeutic effect on COVID‐19, with an intervention score of 20.16. Hesperetin, eriodictyol, luteolin, quercetin, and naringenin were the potentially effective active ingredients against COVID‐19. The hub‐proteins were interleukin‐6 (IL‐6), mitogen‐activated protein kinase 3 (MAPK3), tumor necrosis factor (TNF), and tumor protein P53 (TP53). The potential mechanisms of Yinqiao powder in the treatment of COVID‐19 are the TNF signaling pathway, T‐cell receptor signaling pathway, Toll‐like receptor signaling pathway, and MAPK signaling pathway. This study provides a new perspective for discovering potential drugs and mechanisms of COVID‐19. In December 2019, several patients with severe acute respiratory syndrome, which is now called COVID-19 by the World Health Organization, were found in Wuhan, China (Sun, Lu, Xu, Sun, & Pan, 2020) . The disease is highly transmissible, pathogenic, and recurrent, and large outbreaks have occurred in many countries and regions around the world (Arshad, Baloch, Ahmed, Arshad, & Iqbal, 2020) . On December 18, 2020, China reported a total of more than 95,491 cases, and the total number of cases worldwide has exceeded 50 million, affecting more than 200 countries and regions. Whole-genome sequencing and phylogenetic analysis indicate that COVID-19 is caused by SARS-CoV-2, which is related to the phylogeny of the SARS bat virus, suggesting that bats may be the main host. The main source and the intermediate source of the transfer to humans are unclear, but the rapid transfer from person to person has been widely confirmed (Shereen, Khan, Kazmi, Bashir, & Siddique, 2020) . To make matters worse, specific antiviral drugs or vaccines for COVID-19 are still undergoing clinical trials. After more than 2,000 years of development, traditional Chinese medicine (TCM) has formed a comprehensive and unique system from disease diagnosis to prognosis, which plays an important role in the prevention and treatment of human infectious diseases (Sun, Sun, Yan, Li, & Xin, 2020) . In addition to strict prevention and control measures, many provinces in China have issued TCM prevention and treatment plans for COVID-19 in response to the outbreak of COVID-19, which has achieved remarkable results. Big data mining analysis found that Yinqiao powder was the basic formulation for the Weifen syndrome of COVID-19 . Pharmacological studies have also shown that Yinqiao powder has an antitussive and expectorant effect, improves lung function, alleviates acute lung injury, alleviates pulmonary fibrosis, enhances the antiviral immune response, and alleviates the adverse effects of modern drugs (Rothan & Byrareddy, 2020) . In fact, the active ingredients of Yinqiao powder are complicated. Some active ingredients found in Yinqiao powder by high-performance liquid chromatography analysis may have anti-COVID-19 effects, such as rutin and hesperidin (Shu et al., 2012) . Rehman, AlAjmi, and Hussain (2020) found that the binding affinity of rutin for the main protease (3CL pro ) of SARS-CoV-2 was much higher than that of chloroquine, hydroxychloroquine, and remdesivir, and it may inhibit COVID-19 by downregulating IL-6. Balmeh et al. found that hesperidin has an inhibitory effect on human angiotensin-converting enzyme 2 (ACE2), TMPRSS2, GRP78, and AT1R receptors and may have the ability to treat COVID-19 infection (Balmeh, Mahmoudi, Mohammadi, & Karabedianhajiabadi, 2020) . Although some biologically active substances and their molecular mechanisms for the treatment of COVID-19 have been under investigation, there is a lack of in-depth exploration of Yinqiao powder in the treatment of COVID-19. Network pharmacology is an emerging discipline. Through the "disease-gene-protein-drug" interaction, the effect of drugs on disease can be systematically and comprehensively observed, thereby revealing the complex relationship between Chinese medicine and disease (Lin et al., 2019) . This research method shows integrity and systematic characteristics, which are consistent with the overall theory of Chinese medicine (Li & Zhang, 2013) . In previous studies, network pharmacology has been successfully used to reveal the potential active ingredients, targets, and mechanisms of Chinese medicine in disease treatment, such as the Maxing Shigan Decoction and the Huashi Baidu Formula for COVID-19 (Xun, Jialei, Shaoju, & Bin, 2020) . In this study, we used absorption, distribution, metabolism, and excretion (ADME) information to screen the potential active ingredients and targets of Yinqiao powder for COVID-19 in the TCMSP database, verified the active ingredients with high-resolution liquid chromatography-mass spectrometry (LC-MS), and predicted the efficacy of Yinqiao powder using TCMATCOV. The next step was the use of the disease-association score of the DisGeNET database to screen the co-genes of COVID-19 and Yinqiao powder. Then, we used the STRING database to perform protein-protein interaction (PPI) and topological analyses, performed molecular docking of the identified hub-proteins with their corresponding active ingredients to distinguish the binding activity and site, and used surface plasmon resonance (SPR) analysis to evaluate the affinity. Finally, we performed GO functional, tissue location, and KEGG analyses to identify the mechanism of Yinqiao powder in the treatment of COVID-19, which is shown in Figure 1 . We expect that the results will enhance our understanding of the effective, potential active ingredients of Yinqiao powder for COVID-19 and reveal the biological basis of pharmaceutically acceptable targets, thereby promoting the development of effective COVID-19 therapeutic drugs. The TCMSP database (http://lsp.nwu.edu.cn/, Version 2.3) covers 499 kinds of Chinese medicines registered in the Chinese Pharmacopoeia and provides ADME information on the active ingredients of common Chinese medicines (Ru et al., 2014) . Totally, 176 ingredients of Yinqiao powder were obtained from the TCMSP database, and the potential active ingredients were further screened according to ADME. Oral bioavailability (OB) refers to the relative amount of the drug taken from the liver to the blood circulation after oral drug absorption through the gastrointestinal tract. It is an objective indicator for evaluating drug absorption and affects the effectiveness of clinical drug trials (Xu et al., 2012) . The TCMSP database is based on a dataset composed of 805 different drugs or drug-like molecules. The internal model of the OBioavail 1.1 algorithm was used to calculate the OB value, and ingredients with OB ≥ 70% were screened as potential candidate compounds (Sietsema, 1989) . In particular, if an active ingredient was present in two or more different drugs for Yinqiao powder, the active ingredient only needed to have an oral availability of OB ≥ 35%. Drug-likeness (DL) reflects the pharmacokinetic characteristics of compounds in humans. The TCMSP database uses the Tanimoto parameters to calculate the DL value, which helps to screen out the highly effective active drug ingredients and improve the hit rate of candidate drug molecules (Yongye & Medina-Franco, 2013) . We selected DL ≥ 0.18 to screen potential active ingredients and downloaded their structure in the mol2 format. To verify the active ingredients screened above, LC-MS technology was used to analyze the Yinqiao powder. The decocting program of Yinqiao powder adopts the best strategy screened by the previous orthogonal experiment (Shu et al., 2012) . In short, according to the Schizonepetae herba (Jingjiesui, 12 g) and Menthae haplocalycis herba (Bohe, 18 g), and decocted for 5 min. The mixture was filtered, and 200 μl of the filtrate was mixed with 1 ml of 80% methanol liquid (methanol:water = 8:2); this mixture was vortexed to mix evenly and centrifuged for 10 min at 4 C at 20,000 rpm. Extracts were analyzed by high-resolution LC-MS (Q-Exactive, Thermo Scientific™ Orbitrap Fusion™). The specific protocol was similar to that in previous studies with slight modifications (Fagbohun et al., 2020) . Briefly, the chromatographic column was an RP C18 column of size 150 mm × 2.1 mm, 1.8 μm. The mobile phase consisted of solvent A composed of 0.1% (v/v) formic acid in water and B composed of 0.1% (v/v) formic acid in acetonitrile. The separation started with 98% of eluent A, dropping linearly to 5% within 20 min. The retention time of the drug was 5 min, and after 1 min, it increased again to 98% within 4 min. The total run time was 30 min, the flow rate was 0.3 ml/min, the injection volume was 5 μl, and the column temperature was maintained at 35 C. The LC-MS detection and analysis were F I G U R E 1 Flow chart of this study [Colour figure can be viewed at wileyonlinelibrary.com] conducted in full mass spectrometry-selected ion monitoring mode followed by data-dependent MS 2 (dd-MS 2 ), which was equipped with positive and negative polarity switching scanning from m/z 150.0 to 2,000. The capillary temperature was 300 C, the sheath flow was 40 arb, the spray voltage was 3,800 V, and the auxiliary temperature was 350 C. The overall mass resolution for MS was set to 70,000 and the mass resolution for dd-MS 2 was set to 17,500. The detailed analysis method is shown in Supplementary Material 1. The data were matched with the mzCloud (https://www.mzcloud.org/), mzVault (https://mytracefinder.com/tag/mzvault/), and MassList (www.maldimsi.org/mass) databases. The TCMSP database contains information on 3,311 protein targets, and the relationship between these protein targets and drugs is obtained using the SysDT prediction algorithm . A total of 190 protein targets of the verified potentially active ingredients was obtained and downloaded from the TCMSP database. At the same time, published articles were searched to identify the potential protein targets of the active ingredients. The UniProt database contains three subdatabases: Swiss-Port, PRI-PSD, and TrEMBL, and is the most comprehensive protein database that contains information (Bateman et al., 2019) . The UniProt database (http://www.uniprot.org/uniprot/, updated on June 22, 2017) was used to retrieve the protein ID and gene name of the potential active ingredient and was limited to Homo sapiens, thereby obtaining the gene of the potential active ingredient. Then, the structure of the corresponding protein was downloaded from the PDB database (http://www.rcsb.org/) in the PDB format. The Genetic Association Database (GAD, https://geneticassociationdb. nih.gov/) collects, standardizes, and archives research data on human genetic associations, making it easy for scientific access (Becker, Barnes, Bright, & Wang, 2004) . The GeneCards database (http://www. genecards.org/) integrates gene-centric data from approximately 150 data sources, including genome, transcriptome, proteome, genetics, as well as clinical and functional information (Rebhan, Chalifa-Caspi, Prilusky, & Lancet, 1997) . Online Mendelian Inheritance in Man (OMIM, http://www.ncbi.nlm.nih.gov/omim) is a comprehensive database of human genes and genetic traits. This database focuses on the relationship between phenotype and genotype and contains information about all Mendelian inherited diseases and more than 12,000 human genes (Schorderet, 1991) . We used the keywords "coronavirus" and "SARScoronavirus" in the GAD, GeneCards, and OMIM databases to search for the COVID-19-related genes, and then removed duplicate genes and false positive genes. The gene targets of the disease were matched with the gene targets of Yinqiao powder to obtain co-genes, which were used as the potential gene targets of the active ingredient of Yinqiao powder to treat COVID-19. The DisGeNET database (http://www.disgenet.org/web/DisGeNET/ menu, version 5.0) is a detection platform that can be used to study the molecular basis of human disease and its complications, analyze the characteristics of disease genes, and assess the correlation between genes and disease (Pinero et al., 2020) . We obtained 5,742 associations between genes and diseases in the DisGeNET database, and screened genes associated with viral diseases in a disease class. The potential gene targets of Yinqiao powder's active ingredients for treating COVID-19 and the active ingredients of Yinqiao powder were imported into Cytoscape software (version 3.4.0) to construct the Yinqiao powder's active ingredients and co-gene target network. Topological analysis was used to analyze the connection between the active ingredients and the targets. Qingfei Paidu decoction has been found to have a therapeutic effect on COVID-19 through in silico and experimental studies . Banxia Baizhu Tianma decoction has been used to treat vertigo (Guo, Su, Wang, Luo, & Lai, 2017 ). The STRING database (https://string-db.org/, version 10.5) is a database containing a large number of protein interaction relationships, involving a total of 9,643,763 proteins and 1,380,838,440 interactions, which are detected by experiments or predicted by bioinformatics methods (Szklarczyk et al., 2017) . We imported the potential gene targets of Yinqiao powder into the STRING database, restricted the species to Homo sapiens, and obtained the protein interaction relationship for further study. The medium confidence was set to 0.4, and the results were saved in the TSV format. Node 1, node 2, and the combined score information were imported into Cytoscape software to perform the interactive network. We also used the Generate style from the statistics tool in Cytoscape to set the node size. The Sybyl software (Tripos, version X2.1) was used for molecular docking. This module has the characteristics of high program running speed, accuracy, and reliability. Surflex-Dock scores are expressed in -log10 (K d ) units to represent binding affinities (Jain, 1996) . Surflex-Dock contains the following information: First, the total score of Surflex-Dock is expressed by -log (K d ). Second, "crash" refers to the degree to which a ligand improperly penetrates into a protein and the degree of interpenetration between ligand atoms separated by a rotatable bond. It is advantageous for the crash score to be close to 0. Third, "polar scoring" refers to the contribution of polar interaction to the total score, and it can be used to exclude docking results without hydrogen bonding. 3CL pro is an established drug target for the design of inhibitors to stop viral replication (Kneller et al., 2020) . ACE2 is the binding protein for SARS-CoV-2 to invade the human body (He, Tao, Yan, Huang, & Xiao, 2020) . Therefore, the top four proteins recognized by the PPI network, ACE2 proteins (https://covid-19.uniprot.org/), and 3CL pro (https://www.rcsb.org/structure/6M2Q) were used for molecular docking with Sybyl software to identify the binding ability of the active ingredients and targets and screen potential targets and efficient active ingredients. At the same time, we used the commonly used clinical antiviral drug interferon alpha (IFN-α) (https://pubchem. ncbi.nlm.nih.gov/compound/71306834) as a positive control drug. The The UniProt ID of Yinqiao powder was imported into the KEGG data- In the DisGeNET database, 209 associations were obtained. After deleting duplicate and false results, 33 genes were associated with viral diseases or coronavirus infections, which are shown in Table S3 . There were eight genes with DisGeNET scores ≥ 0.1 (TNF, TP53, IL6, IL10, STAT1, IFNG, CXCL10, and BCL2), and two genes were related to COVID-19 (MCL1 and ACE2). Using TCMATCOV, we compared the intervention effect of Yinqiao The PPI network is shown in Figure 2b . The nodes represent proteins, and the lines represent the associations between proteins. A total of 43 nodes and 440 edges were involved. The average node degree was 20.47. Topological analysis found that four proteins ranked in the top four in degree, betweenness centrality, and closeness centrality, namely IL6, mitogen-activated protein kinase 3 (MAPK3), tumor necrosis factor (TNF), and tumor protein P53 (TP53) ( Table S5 ). The molecular docking results in comparison to those of IFN-α, which is currently a common treatment for COVID-19, are highlighted in Table S6 and Figure 2c . It is generally believed that when the docking score is above 1.0, the molecule has a certain binding activity between the ingredients and the protein targets. A docking score >3.0 indicates that the ingredients have good binding activity to the protein targets, while a docking score >5.0 indicates strong binding activity (Lin et al., 2019) . The crash scores were close to 0, indicating that the docking results were reliable. The polar score and total score were similar, indicating that the total score basically reflects the docking of the ingredients and protein targets. Luteolin and ACE2 obtained the highest docking total score, mainly by hydrogen bonds or π-π bonds, which was higher than highest docking total score for the binding of IFN-α and ACE2. SPR assays indicated that luteolin is bound to ACE2 with a dissociation constant (K d ) of 121 μM (Figure 2d) Abbreviations: area, compound peak area; mzCloud best match, MzCloud database matching score (the higher the value, the higher the credibility of the result identified); RT, chromatographic retention time. F I G U R E 2 Legend on next page. active ingredients have good binding ability with 3CL pro , which means that they may be highly effective active ingredients for Yinqiao powder to treat COVID-19. and Chinese programs to control COVID-19 found that Jinyinhua, Lianqiao, and Gancao were commonly used to control COVID-19 . Zhang, Liang, Kong, and Xiao (2019) found that moxifloxacin combined with Jiegeng was significantly better than moxifloxacin alone in improving cough symptoms in patients with pneumonia and could reduce the WBC and CRP levels in patients. In our study, 30 ingredients of Yinqiao powder were screened from the TCMSP database based on the OB and DL, and five ingredients, namely hesperetin, eriodictyol, luteolin, quercetin, and naringenin, were verified by LC-MS analysis. All of them were flavonoids and were associated with potential anti-COVID-19 genes. A previous study confirmed that flavonoids have antiinflammatory, antioxidant, antiproliferative, antithrombotic, cardioprotective, and neuroprotective effects (Gujar & Wairkar, 2020) . In addition, some of these ingredients have been proven to have anti-COVID-19 effects. For example, hesperetin was found to have high affinity for the spike protein and the helicase and protease sites on the ACE2 receptor (Ngwa et al., 2020) . Luteolin was found in a variety of anti-COVID-19 Chinese medicine prescriptions, such as Maxing Shigan decoction and Tanreqing Therefore, the antagonistic effect of Yinqiao powder on COVID-19 may be closely related to the regulation of these inflammation-related proteins. To further screen the potential active ingredients, we used molecular docking to identify the binding activity of the active ingredients and anti-COVID-19 protein. We found that luteolin and ACE2 have the best binding ability, mainly through hydrogen bonds or π-π bonds, which means that luteolin has a certain role in preventing COVID-19 infection. Jimilihan et al. (2020) also confirmed that luteolin has good binding activity with ACE2 and that hydrogen bonding plays a key role in the recognition and stability of the active ingredients and proteins. SPR analysis showed that luteolin combined with ACE2 had a K d of 121 μM, and the corresponding -log10 (K d ) value was 3.917, which was lower than the total score of 5.63. This indicated that the molecular docking results obtained by Surflex-Dock may overestimate the actual affinity between the ingredients and the targets. This phenomenon has also been reported in previous studies (Jain, 1996) . However, this affinity was still far lower than that of COVID-19 and ACE2 (K d 121 μM vs. 15 nM) (Wrapp et al., 2020) . In fact, the role of Yinqiao powder in preventing and treating COVID-19 not only depends on the competitive combination of luteolin and ACE2 but also may be related to the joint control of the inflammatory response and antiviruses with multiple ingredients and targets. Interestingly, we also dis- Couture et al. (2020) found that luteolin could inhibit membrane synthesis and cell proliferation to activate apoptosis, which may be related to the increased expression of related genes such as Fas, Cdkn1a, Atp7b, and TP53, and the increased accumulation of cleaved caspase 3 and PARP. Wrapp et al. (2020) believe that the key to COVID-19 infection lies in the binding between the SARS-CoV-2 spike protein and ACE2 protein, and understanding the structure and affinity of these two proteins will help in the development of antiviral drugs. However, the role of the extracellular region in COVID-19 is still unclear. In addition, it is interesting to find that the anti-COVID-19 genes were mainly expressed in the lung and liver; this finding has also been confirmed in previous studies. For example, Zhang observed that COVID-19 patients have obvious abnormalities in coagulation, which may be caused by liver damage and inflammatory storms . In addition, inflammatory storms can cause lung damage . patients (Karki et al., 2020) . DiNicolantonio and McCarty (2020) found that the Toll-like receptor signaling pathway was involved in thrombosis in patients with COVID-19. In addition, Yang et al. (2020) found that the thrombin and Toll-like receptor signaling pathways may be important antiinflammatory pathways of Maxing Shigan decoction for the treatment of COVID-19 through transcriptomics analysis. The role of the T-cell receptor signaling pathway in COVID-19 is still unclear, but Sallenave and Guillot (2020) found that JAK1-STAT5 could increase CD8 + T cells and decrease lymphocytes in critical patients with COVID-19 by inhibiting the expression of IL-2/IL-2R. Grimes and Grimes (2020) believe that the p38 MAPK pathway plays a key role in the release of proinflammatory cytokines (such as IL-6), pro-vasoconstriction, and prothrombotic activity, and is related to acute lung injury and myocardial dysfunction. Although these signaling pathways were related to the occurrence and development of COVID-19, there is currently no experiment to further verify the specific role of Yinqiao powder against COVID-19 in these signaling pathways. In this study, we found that hesperetin, eriodictyol, luteolin, quercetin, and naringenin were potential effective active ingredients against COVID-19 The antagonistic effect of Yingqiao powder on the inflammatory storm caused by COVID-19 may be related to the regulation of IL-6, MAPK3, TNF, and TP53 targets. The specific pathways were the TNF signaling pathway, the T-cell receptor signaling pathway, the Toll-like receptor signaling pathway, and the MAPK signaling pathway. Our study provides a new perspective for discovering potential drugs and mechanisms of COVID-19. 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The data and materials generated or analyzed during this study are available from the corresponding author on reasonable request. https://orcid.org/0000-0002-9939-7698Xiaotong Wang https://orcid.org/0000-0002-5329-2663Zhen Shen https://orcid.org/0000-0002-6109-9775