Abstract:
Background: Network pharmacology (NP) investigates the multifaceted actions of drugs across
various targets, aiding drug discovery for complex diseases like gastroenteritis (GE). Metformin
(MET) has antihyperglycemic and potential antimicrobial effects, while ceftriaxone (CEF) is
effective against gram-negative strains but prone to resistance. Combining CEF with MET may
synergize their antimicrobial effects, potentially reducing doses and resistance.
Objective: To predict the potential synergy between MET-CEF combination against GE using NP
approaches
Methods: Pharmacodynamic gene targets of MET and CEF were predicted via Swiss Target
Prediction, Pharmapper, and SEA Search Server. GE-associated genes were sourced from
DisGeNET, OMIM, and GeneCard databases. Intersection genes between drugs and GE were
determined using Venny 2.1. Protein-protein interaction (PPI) network was constructed using the
STRING database. The resulting network was analyzed using Cytoscape. Cytoscape’s cytoHubba
v0.1 was used to determine the top ten interacting genes. Subsequent analysis involved Gene
Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis.
Results: The study revealed 188, 194, and 382 potential target genes for MET, CEF, and the
MET-CEF combination, respectively, with 988 genes associated with GE. The intersection of
target genes between GE and MET, CEF, or the MET-CEF combination was 27, 43, and 55,
respectively, indicating broader gene modulation with the MET-CEF combination compared to
individual drugs. The PPI network comprised 55 nodes and 376 edges, with CASP3, interleukin 2,
and NFκB1 identified as the most interacting genes, predominantly involved in cellular apoptotic
and inflammatory pathways. The primary biological process targeted by the MET-CEF
combination was the regulation of the inflammatory response. Enriched pathways included
Yersinia infection, PD-L1 expression, PD-1 Checkpoint pathway, and C-type lectin receptor
signalling, associated with GE pathophysiology.
Conclusions: The MET-CEF combination has the potential to target multiple pathways associated
with GE pathophysiology, indicating its enhanced efficacy as a promising therapeutic option for
GE treatment with potential synergistic effects.
