Systems pharmacology-based drug discovery and active mechanism of natural products for coronavirus pneumonia (COVID-19): An example using flavonoids

Abstract

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.

Keywords: COVID-19; Flavonoids; Molecular docking; Natural products; Systems pharmacology.

Graphical abstract

Fig. 1

Whole technical route of present research based on network pharmacology and molecular docking for revealing flavonoids against COVID-19 in multiple targets and pathways.

Fig. 2

Distribution of structure type for 255 candidate flavonoids. The y-axis represented the number of candidate compounds in each category. A—Flavone; B—Flavanone; C—Flavonol; D—Flavanonl; E—Isoflavone; F—Isoflavanone; G— Chalcone; H—Dihydrochalcone; I—Anthocyanidin; J—Flavanol; K—Biflavonoid; L—Miscellaneous Flavonoid.

Fig. 3

Venn diagram of flavonoids and COVID-19-related targets.

Fig. 4

PPI network and MCODE modules of intersection targets. (A) An overall view of the whole PPI network. (B–D) Three high correlation MCODE in PPI network. The size and color depth of node were correlated with three network topology parameters (degree-value of connection, betweenness, and closeness).

Fig. 5

GO function and KEGG pathway enrichment of intersection targets. (A) Enrichment diagram of BP, CC, and MF terms. The vertical axis represents the enrichment score. (B) The cluster analysis of high correlation GO terms. (C) The bubble diagram of KEGG Pathway. The smaller the P-value (the redder the color), the higher the enrichment score. (D) The cluster analysis of KEGG pathway. The size of the region represents the proportion of pathways.

Fig. 6

C-T network of active flavonoids and associated targets. The size and color depth of node were correlated with three network topology parameters (degree-value of connection, betweenness, and closeness).

Fig. 7

T-D network of associated targets and significant disease categories. The size and color depth of node were correlated with three network topology parameters (degree-value of connection, betweenness, and closeness).

Fig. 8

Molecular docking of flavonoids binding with targets and their binding energy.

Fig. 9

Combination effects between flavonoids and COVID-19-related proteins. (A) Combination effect between genkwanin with 3CL Pro. (B) Combination effect between quercetin with ACEⅡ.

Fig. 10

Underlying mechanisms of flavonoids in the treatment of COVID-19. Ingredients from flavonoids attenuate the symptoms by acting on inflammatory, antiviral, and immune regulation and repairing tissue injury.