key: cord-0841959-wqrwdgnj authors: Wang, Bin; Ding, Yan; Zhao, Penghui; Li, Wei; Li, Ming; Zhu, Jingbo; Ye, Shuhong title: Systems pharmacology-based drug discovery and active mechanism of natural products for coronavirus pneumonia (COVID-19): An example using flavonoids date: 2022-01-26 journal: Comput Biol Med DOI: 10.1016/j.compbiomed.2022.105241 sha: 204f9e14ef1d61ca1a45a81d33a106f946b2374f doc_id: 841959 cord_uid: wqrwdgnj BACKGROUND: Recently, the value of natural products has been extensively considered because these resources can potentially be applied to prevent and treat coronavirus pneumonia 2019 (COVID-19). However, the discovery of nature drugs is problematic because of their complex composition and active mechanisms. METHODS: This comprehensive study was performed on flavonoids, which are compounds with anti-inflammatory and antiviral effects, to show drug discovery and active mechanism from natural products in the treatment of COVID-19 via a systems pharmacological model. First, a chemical library of 255 potential flavonoids was constructed. Second, the pharmacodynamic basis and mechanism of action between flavonoids and COVID-19 were explored by constructing a compound–target and target–disease network, targets protein-protein interaction (PPI), MCODE analysis, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RESULTS: In total, 105 active flavonoid components were identified, of which 6 were major candidate compounds (quercetin, epigallocatechin-3-gallate (EGCG), luteolin, fisetin, wogonin, and licochalcone A). 152 associated targets were yielded based on network construction, and 7 family proteins (PTGS, GSK3β, ABC, NOS, EGFR, and IL) were included as central hub targets. Moreover, 528 GO items and 178 KEGG pathways were selected through enrichment of target functions. Lastly, molecular docking demonstrated good stability of the combination of selected flavonoids with 3CL Pro and ACEⅡ. CONCLUSION: Natural flavonoids could enable resistance against COVID-19 by regulating inflammatory, antiviral, and immune responses, and repairing tissue injury. This study has scientific significance for the selective utilization of natural products, medicinal value enhancement of flavonoids, and drug screening for the treatment of COVID-19 induced by SARS-COV-2. betweenness centrality. Furthermore, the Metascape platform (http://metascape.org) 156 was used to explore biological process of interaction between potential targets [37] . with enzymes, kinases, and signaling pathways accounting for a high proportion. The number of edges and the average node degree-values in the PPI network 223 were 643 and 8.46, respectively. Additionally, 52 protein targets were greater than the 224 average degree-value. Furthermore, topological parameters were calculated using the 225 CytoHubba tool, as shown in Table S2 . A recent study on surface plasmon 282 resonance (SPR) and fluorescence resonance energy transfer (FRET) binding showed 283 that compounds with good binding ability to 3CL Pro included EGCG (J3) and other [49] . The active site of the protein was centered on the active site of the original ligand 288 in the crystal structure. Given the high homology of the conformation of flavonoids, 289 the binding effects (binding sites and forces) between flavonoids and 290 COVID-19-related proteins were predominantly similar. As an example (Fig. 9A) , for 291 the 3CL Pro combined with genkwanin (A17), the hydroxyl groups formed hydrogen 292 bonds with residues of ASP187, and CYS44 at the active site of 3CL hydrolase, while 293 carbonyl and methyl also interacted with GLU166 and GLY143. When ACEⅡ was The main active mechanism is conventional therapy with symptomatic support. J o u r n a l P r e -p r o o f World Health Organization, WHO Coronavirus (COVID-19) Dashboard Suite: From Gene Data Mining to Disease Genome Sequence Analyses, Curr 54 (2016) 1.30.1-1.30.33 DrugBank 5.0: A major update to the DrugBank database for 625 2018 Von Mering, the ACE2 receptor Pathological findings of COVID-19 associated with acute respiratory distress 710 syndrome Clinical features of patients infected with 2019 novel coronavirus in 716 Randomized Clinical Trial A review of anti-infective and anti-inflammatory chalcones Flavonoids in food and their health benefits Bioactive natural 759 compounds against human coronaviruses: a review and perspective SARS-CoV-2 induced inflammatory storm Traditional Chinese medicine for COVID-19 771 treatment Recent progress regarding 774 kaempferol for the treatment of various diseases Anti-hepatitis B virus activity of wogonin in vitro and in vivo Quercetin and related polyphenols: New 780 insights and implications for their bioactivity and bioavailability DPP4-directed therapeutic strategies for MERS-CoV 787 GSK3B and MAPT Polymorphisms Are Associated with Grey Matter and Healthy Individuals The biochemistry and medical significance of the flavonoids COVID-19 in patients discharged from hospital: a cohort study Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) 806 transcription Modulation of nitric oxide by 840 flavonoids COVID-19 pathways for brain and heart 844 injury in comorbidity patients: A role of medical imaging and artificial 845 intelligence-based COVID severity classification: A review Recovery Effect of Onion Peel Extract against H 2 O 2 -Induced Inhibition 849 of Gap-Junctional Intercellular Communication is Mediated through Quercetin