Therapeutic Potential of Gynostemma pentaphyllum (Thunb.) Makino Against COVID-19 Identified Through Network Pharmacology

Abstract

Background/Objectives: The ongoing challenges posed by COVID-19 have highlighted the need for multi-target therapeutic strategies addressing both acute immune responses and systemic complications. Gynostemma pentaphyllum (Thunb.) Makino, a traditional herbal medicine rich in flavonoids and saponins, exhibits diverse pharmacological activities, including immunomodulatory and cardiovascular effects. In this study, we investigated the potential of G. pentaphyllum as a complementary treatment for COVID-19 using a network pharmacology approach combined with molecular docking analysis. Methods: To delve into the therapeutic mechanisms of G. pentaphyllum, we identified 59 active compounds and predicted 408 protein targets, of which 19 overlapped with COVID-19-associated genes, including IL1B, IL6, TNF, ACE, and REN. GO and KEGG enrichment analyses were conducted to determine relevant biological processes and pathways, focusing on cytokine signaling, inflammatory responses, and the renin-angiotensin system. Network analyses evaluated interactions of flavonoids and triterpenoid saponins with immunological, inflammatory, renin-angiotensin system, and host entry pathways. Molecular docking was performed to validate the binding affinities of key compounds to their predicted targets. Results: The compound-target-pathway network revealed class-specific patterns: flavonoids primarily mapped to immuno-inflammatory nodes, whereas triterpenoid saponins were enriched for renin-angiotensin system/host-entry-related targets. Docking energies spanned -6.1 to -11.9 kcal/mol, with six compound-target pairs ≤ -10.0 kcal/mol. Notably, NOS2-rutin (-11.9 kcal/mol), NOS2-gypenoside LI (-11.6 kcal/mol), and ACE-gypenoside LI (-11.3 kcal/mol) showed the strongest affinities. Conclusions: These findings provide evidence that G. pentaphyllum exerts therapeutic effects through the complementary actions of flavonoid and saponin components, each modulating distinct molecular pathways. This dual mechanistic potential underscores the value of G. pentaphyllum as a versatile therapeutic for COVID-19 therapy.

Keywords: COVID-19; Gynostemma pentaphyllum; flavonoids; molecular docking; network pharmacology; triterpenoid saponins.

Figure 1

Network pharmacology for identifying mechanisms of G. pentaphyllum in treating COVID-19.

Figure 2

Network pharmacology-based identification of candidate targets and active components of G. pentaphyllum against COVID-19. (A) Construction of Compound-Target network. Different active compounds (orange circular nodes) are displayed around the periphery, with node size reflecting the number of predicted targets. Putative target proteins (green rectangular nodes) are positioned inside the circle defined by the active compounds. (B) Venn diagram showed the overlap between the putative target proteins of G. pentaphyllum and COVID-19-associated targets. (C) Major active compounds of G. pentaphyllum related to COVID-19.

Figure 3

The Protein–Protein Interaction (PPI) network. The top 17 intersecting target proteins were shown in circular nodes with different sizes. The size of the nodes expressed the interaction degree on the network.

Figure 4

GO and KEGG Pathway Enrichment Analysis. (A) Biological process, (B) cellular components, and (C) molecular functions of Gene Ontology (GO) analysis. (D) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.

Figure 5

The compound-target-pathway (CTP) network. The compound–target–pathway (CTP) network constructed for G. pentaphyllum. Circular nodes represent active compounds, rectangular nodes represent predicted protein targets, and hexagonal nodes represent KEGG pathways. Targets predominantly linked to triterpenoid compounds are shown in blue, flavonoid-related targets in green, and shared targets in purple.

Figure 6

Representative molecular docking diagrams of G. pentaphyllum active compounds and key targets associated with COVID-19 using AutoDock Vina (version 1.1.2). (A) Docking model of ombuoside (GPM15, flavonoid) with NOS2. (B) Docking model of gypenoside LI (GPM32, triterpenoid) with ACE. The visualization includes the overall protein–ligand complex, binding site interactions (3D), and 2D interaction mapping.