Virtual screening of small molecular inhibitors of SARS-CoV-2 3CL hydrolase based on high-throughput molecular docking and prediction of Chinese materia medica and its compound against COVID-19 / 中草药

Objective: Based on the systematic pharmacological database of traditional Chinese medicine (TCM) and the analysis platform TCMSP, the computer virtual screening technique was used to screen the small molecule inhibitors of SARS-CoV-2 3CL hydrolase from Chinese materia medica (CMM), and speculate the potential anti-COVID-19 novel coronavirus pneumonia TCMs and its compounds. Methods: SARS-CoV-2 3CL hydrolase protein was targeted in this study. Autodock Vina software and Python script were used to realize high-throughput molecular docking. Combined with “ADME-Lipinski” rules, the re-screening was carried out to optimize the active ingredients and speculate the key TCMs and compound prescriptions. Based on the perspective of network pharmacology, a component-target-pathway network was constructed to infer the mechanism of action of core drug pairs. Results: Taking the reference ligand as positive control, 66 natural micromolecule compounds with good pharmacokinetic properties were obtained. Twelve single TCMs, two Chinese medicine pairs of Glycyrrhizae Radix et Rhizoma-Mori Cortex and Lonicerae Japonicae Flos-Forsythiae Fructus, and 12 TCM prescriptions including Sangju Drink and modified Sangju Drink and Yinqiao Powder were selected as candidate schemes to fight against novel coronavirus pneumonia. Conclusion: This study is based on high-throughput molecular docking technology to virtually screen small molecule inhibitors of SARS-CoV-2 3CL hydrolase of CMM and Chinese medicines, innovatively analyze the potential molecular mechanism in combination with network pharmacology, and provide scientific guidance and theoretical basis for TCM to resist novel coronavirus pneumonia.

Exploring potential effect of Shengjiang San on SARS-CoV-2 based on network pharmacology and molecular docking / 中草药

Objective: To explore the potential effect of Shengjiang San for inhibiting SARS-CoV-2. Methods: The target genes of Beauveria bassiana, Cryptotympana pustulata, Curcuma longa, Rheum officinale in Shengjiang San were screened out through the database analysis of Encyclopedia of Traditional Chinese Medicine (ETCM), and traditional Chinese medicine system pharmacology platform (TCMSP), Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) and Collective Molecular Activities of Useful Plants (CMAUP). GeneCards database was used to obtain target genes of antivirus. The intersection method was used to obtain the target genes related to the antiviral effect of Shengjiang San. Cytoscape 3.7.2 software was applied for the construction of prescription-CMM-targets (genes) networks. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene ontology (GO) functional enrichment analysis were performed by R language to predict the potential mechanism of Shengjiang San against the virus. TCMSP, CNKI and PubChem databases were used to retrieve the chemical components of B. bassiana, C. pustulata, C. longa and R. officinale in Shengjiang San. AutoDock Vina 1.1.2 was used for molecular docking to study the interactions of each chemical component with SARS-CoV-2 3CL hydrolase or angiotensin converting enzyme II (ACE2). Results: Shengjiang San could play an antiviral role through the corresponding 663 target genes. Top ten pathways were related to antivirus (P < 0.01) in the KEGG pathway enrichment screening, including influenza A, etc. The affinity values of a total of 133 compounds in Shengjiang San were < -29.3 kJ/mol for molecular docking with SARS-CoV-2 3CL hydrolase. The affinity values of 145 compounds for molecular docking with ACE2 were < -29.3 kJ/mol. Conclusion: Shengjiang San could regulate multiple signaling pathways to inhibit virus, and have a potential inhibiting effect on SARS-Cov-2.

Research on active compounds of Maxingyigan Decoction for treatment of coronavirus disease 2019 based on network pharmacology and molecular docking / 中草药

Objective: To explore the active compounds of Maxingyigan Decoction for the treatment of coronavirus disease 2019 (COVID-19). Methods: The chemical constituents and action targets of Ephedra sinica, Armeniacae Semen Amarum, Coicis Semen, and Glycyrrhizae Radix et Rhizoma in Maxingyigan Decoction were retrieved from TCMSP. The database of UniProt and GeneCards were used to query the target genes that corresponding to the active compounds, and then a compound-target (gene) network was constructed by Cytoscape 3.6.1. GO functional enrichment analysis and KEGG enrichment analysis were performed through WebGestalt database to predict its mechanism of action. The main active ingredients were docked with SARS-CoV-2 3CL hydrolase and angiotensin converting enzyme II (ACE2). Results: The compound-target network contained 126 compounds and 266 corresponding targets. The key targets genes included PTGS2, ESR1, PCP4, PPARG, HSP90AA1, NCOA2, etc. GO function enrichment analysis found that 522 GO items were affected by Maxingyigan Decoction, including 12 biological process items, 20 cell composition items, and 17 molecular function items. KEGG enrichment analysis showed that 168 signal pathways were enriched, involving interferon-γ signaling pathway, MAP kinase cascade, T cell activation, chemokines and cytokine signaling pathway-mediated inflammation pathways, etc. The molecular docking results showed that core compounds such as luteolin and quercetin had similar affinity with the recommended drugs used to treat COVID-19. Conclusion: The active compounds in Maxingyigan Decoction may have a therapeutic effect on COVID-19 through binding with 3CL hydrolase and ACE2 to act on targets such as PTGS2, ESR1, PCP4, PPARG, HSP90AA1 and NCOA2 so as to regulate multiple signal pathways.

Exploring active compounds of Jinhua Qinggan Granules for prevention of COVID-19 based on network pharmacology and molecular docking / 中草药

Objective: To explore the effective chemical constituents of Jinhua Qinggan Granules for treatment of coronavirus disease 2019 (COVID-19). Methods: The compounds and action targets of eleven herbal medicines in Jinhua Qinggan Granules were collected via TCMSP. The genes corresponding to the targets were queried by the UniProt database, then the “herbal medicine-compound-target” network was established by Cytoscape software. The gene ontology (GO) function enrichment analysis and KEGG pathway enrichment analysis were performed by DAVID to predict their mechanism. Molecular docking was used to analyze the binding force of the core effective compounds in the “herbal medicine-compound-target” network with SARS-CoV-2 3CL hydrolase and angiotensin converting enzyme II (ACE2). Results: The “herbal medicine-compound-target” network contained 154 compounds and 276 targets, and the key targets involved PTGS2, HSP90AB1, HSP90AA1, PTGS1, NCOA2, etc. GO function enrichment analysis revealed 278 items, including ATP binding, transcription factor activation and regulation of apoptosis process, etc. KEGG pathway enrichment screened 127 signaling pathways, including TNF, PI3K/Akt and HIF-1 signaling pathways related to lung injury protection. The results of molecular docking showed that formononetin, stigmasterol, beta-sitosterol, anhydroicaritin and other key compounds have a certain degree of affinity with SARS-CoV-2 3CL hydrolase and ACE2. Conclusion: The effective compounds in Jinhua Qinggan Granules regulate multiple signaling pathways via binding ACE2 and acting on targets such as PTGS2, HSP90AB1, HSP90AA1, PTGS1, NCOA2 for the prevention of COVID-19.

Mechanism of sovereign medicines in Sanren Decoction on COVID-19 based on network pharmacology and molecular docking / 中草药

Objective: To investigate the mechanism of sovereign medicines in Sanren Decoction on coronavirus disease 2019 (COVID-19) through network pharmacology and molecular docking methods. Methods: The main active ingredients of sovereign medicines in Sanren Decoction (Armeniacae Semen Amarum, Amomun kravanh Pierre ex Gagnep, and Coicis Semen) were obtained and screened from by TCMSP and TCMID V2.0, combined with related research. Using UniPort database to query the target proteins corresponding to the active ingredients, then a component-target network was constructed by Cytoscape 3.7.2. PPI network was constructed through the STRING website, and cytoHubba was used to analysis the key subnetworks. CTD database was used to analyze GO and KEGG enrichment of the active ingredient target proteins of Sanren Decoction. Using the active ingredients of sovereign medicines in Sanren Decoction and related chemical drugs such as lopinavir as ligands, molecular docking with the SARS-CoV-2 3CL hydrolase was performed through the CB-Dock website. Results: Sovereign medicines in Sanren Decoction had 39 active ingredients, corresponding to 168 target proteins. The GO enrichment analysis obtained 25 biological processes (BP) items, 14 related items of cell composition (CC), and two molecular function (MF) item, respectively. KEGG enrichment screened 36 signaling pathways such as innate immune system, cytokine signaling in immune system, signaling by interleukins. The molecular docking results suggested that the active ingredients of mairin, ziziphin_qt, and oleanolic acid of sovereign medicines in Sanren Decoction had good binding energy with SARS-CoV-2 3CL hydrolase, and the Vina score of them were similar to those of lopinavir (the 3CLpro inhibitor) and remdesivir (RNA-dependent RNA polymerase inhibitor). Conclusion: Sovereign medicines in Sanren Decoction may participate in inflammation-related signaling pathways by regulating inflammatory factors, regulating multiple physiological processes of the disease with multi-components, multi-targets, and multi-pathways. It plays a certain intervention role in the treatment of COVID-19 and its active ingredients have potential resistance to SARS-CoV-2.

Molecular mechanism of Bufei Huoxue Capsule on COVID-2019 based on network pharmacology and molecular docking / 中草药

Objective: To explore the potential mechanism of Bufei Huoxue Capsule (BHC) on coronavirus disease 2019 (COVID-19), and provide a theoretical basis for the clinical application of BHC. Methods: TCMSP, BATMAN-TCM, CNKI and Pubmed databases were used to search the compounds and targets of BHC and GeneCards database was used to search the targets of COVID-19; The intersection method was used to obtain the targets related to the therapeutic effect of BHC. Cytoscape 3.7.2 software was applied for the construction of CMM-compounds-targets network map. Protein-protein interaction (PPI) network was constructed by STRING database. Gene ontology (GO) functional enrichment analysis and KEGG pathway enrichment analysis were conducted by DAVID. AutoDock Tools 1.5.6 and AutoDock vina 1.1.2 were used for molecular docking. Results: A total of 32 potential active components were screened from BHC, corresponding to 203 targets. Among them, there were 11 core compounds and 52 core targets. PPI network analysis showed that there were 25 key targets intervening COVID-19 by BHC. A total of 251 biological processes (P < 0.05) and 93 pathways (P < 0.05) were obtained by GO analysis and KEGG analysis, respectively. The results of molecular docking showed that the key compounds had good affinity with SARS-CoV-2 3CL hydrolase and angiotensin converting enzyme II. Conclusion: The active compounds of BHC can target IL6, MAPK8, PTGS2, PTGS1 and NCOA2 to regulate multiple signal pathways, and play a therapeutic role in the recovery period of COVID-19.

Study on screening potential traditional Chinese medicines against 2019-nCoV based on Mpro and PLP / 中国中药杂志

With the rapid outbreak of COVID-19, traditional Chinese medicine(TCM) has been playing an active role against the epidemic. However, the screening of TCM is limited by the development cycle and laboratory conditions, which greatly limits the screening speed. This study established optimization docking models and virtual screening to discovery potential active herbs for the prevention and treatment of the novel coronavirus based on molecular docking technology. The crystal structures of 3 CL protease(Mpro) and papain-like protease(PLP) were obtained from PDB database and homologous modeling respectively, and were used to conduct virtual screening of TCMD 2009 database by CDOCKER program. The ingredients scored in the top 100 were selected respectively, and the candidate herbs were ranked by the numbers of hit molecules. Based on Mpro inhibitors screening, 12 322 potential active components were obtained, and the representative active components included aster pentapeptide A, ligustrazine, salvianolic acid B, etc., and Zingiberis Rhizoma Recens, Asteris Radix et Rhizoma, Notoginseng Radix et Rhizoma, Chuanxiong Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Zingiberis Rhizoma, Dianthi Herba, Rhei Radix et Rhizoma, Cistanches Herba were obtained. While 11 294 potential active ingredients were obtained by PLP inhibitor screening, representative active ingredients included gingerketophenol, ginkgol alcohol, ferulic acid, etc., and Codonopsis Radix, Notopterygii Rhizoma et Radix, Zingiberis Rhizoma Recens, Ginkgo Semen, Chuanxiong Rhizoma, Trichosanthis Fructus, Paeoniae Radix Alba, Psoraleae Fructus, Sophorae Flavescentis Radix, Notoginseng Radix et Rhizoma, Angelicae Sinensis Radix were chosen. By combining the diagnosis and treatment scheme of Hunan province's and angiotensin converting enzyme 2(ACE2) inhibitors screening from literature, present study also discussed the rational application of candidate herbs to this epidemic situation. Trichosanthis Fructus obtained by PLP inhibitors screening and Fritillaria verticillata obtained by ACE2 inhibitors screening were parts of the Sangbei Zhisou Powder and Xiaoxianxiong Decoction, which might be applicable to the syndromes of cough and dyspnea. Rhei Radix et Rhizoma screened by Mpro and Trichosanthis Fructus screened by PLP were contained in Maxing Shigan Decoction and Xuanbai Chengqi Decoction, and could be applied to the syndromes of epidemic virus blocking lung. Mori Folium, Lonicerae Japonicae Flos and Forsythiae Fructus obtained by ACE2 inhibitors screening were included in the Sangju Decoction and Yinqiaosan, which might be applicable to the syndromes of warm pathogen attacking lung and cough and dyspnea. The results of this study are intended to provide a reference for the further development of traditional Chinese medicine to deal with the new epidemic.

Potential active compounds of Liupao tea for prevention and treatment of COVID-19 based on network pharmacology and molecular docking / 中国药科大学学报

@#To investigate the material basis and mechanism of Liupao tea on preventing COVID-19 by network pharmacology and molecular docking.The active ingredients and targets of Liupao tea were searched through the literature and the TCMSP databases and the network between the two was built by Cytoscape 3.7.1.Then using GenCards platform to predict the disease targets,mapping the common targets between Liupao tea and disease.The common targets were imported into the STRING database for exploring the protein-protein interaction.Core targets were enriched by gene ontology (GO) enrichment analysis and KEGG (kyoto encyclopedia of genes and genomes) pathway enrichment analysis using DAVID database etc..Finally,the screened active components were docked with the receptor protein SARS-CoV-2 3CL hydrolase (Mpro).Six active ingredients of Liupao tea were screened,such as (-)-epigallocatechin gallate (EGCG),(+)-catechin,(-)-catechin gallate,α-spinasterol,pelargonidin chloride and squalene,and 156 targets were identified.Among them,there were 112 common targets and 38 core targets with COVID-19.GO enrichment analysis (P<0.01) involved lipopolysaccharide,cell response to hypoxia,etc..And the KEGG pathway enrichment analysis (P<0.01)was conducted to obtain the HIF-1,IL-17,T cell receptor and other signaling pathways associated with COVID-19.The results of molecular docking showed that the active ingredients of Liupao tea were well bound to the receptor protein Mpro.The active ingredients of Liupao tea may control HIF-1,IL-17,T cell receptors signaling pathways by binding Mpro hydrolase and acting on inflammation and immune related targets such as MAPK1,TNF to prevent COVID-19.The EGCG of Mpro activity was determined ,and the IC50 was 3.4 μmol/L,which confirmed that EGCG was a certain inhibition effect on Mpro.