Systems analysis of Berberis vulgaris alkaloids unveils their functional synergy and drug-like potential

Berberis species are rich in isoquinoline alkaloids with promising therapeutic properties for various diseases, including SARS-CoV-2. Despite their known medicinal attributes, the potential for combining them at suitable doses remains underexplored. This study investigated the compound-target interactions, functional enrichment, and pharmacokinetic profiles of seven B. vulgaris alkaloids (berberine, palmatine, berberrubine, lambertine, obamegine, berbidine, and berbamine) using an in-silico approach. Compound-target interactions were identified using SwissTargetPrediction. Protein-protein interaction (PPI) networks were constructed using STRING in Cytoscape, and an UpSet plot was generated in Python to visualize overlapping targets and potential synergy. Functional enrichment analysis was performed in DAVID using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, followed by compound-gene-pathway network construction in Cytoscape. Pharmacokinetic profiles of compounds were assessed using ADMET-AI. A total of 42 genes were shared by at least two compounds. Genes associated with neurotransmission (DRD, ADRA, and ADRB) were identified as hubs mediating key functional interactions. Berbamine and obamegine shared the highest number of targets (10). Functional enrichment by KEGG and GO identified 16 and 20 significantly enriched pathways and biological processes, respectively, and formed networks consisting of distinct nodes (pathway = 67, GOBP = 69) and edges (pathway = 228, GOBP = 229). Favorable drug-likeness was identified for all alkaloids, excluding berbamine and obamegine (0.3), and low clinical toxicity (0.0-0.3). The results highlight the therapeutic potential of B. vulgaris alkaloids to provide complementary and synergistic effects across different disease pathways and support their development in botanical medicine.