Systems Biology Approach to Berberine Metabolomics and Toxicity: An In Silico Investigation of Bioactive Pathways and Risk Assessment

Berberine, a bioactive isoquinoline alkaloid found in various medicinal plants, has gained special attention for its bioactive properties, including antimicrobial, anti-inflammatory, and anticancer activities. However, for safe and therapeutic applications, the metabolic profiling and associated toxicity need to be evaluated thoroughly. The present study employs an integrative and holistic approach to annotate the ADME profiling, in silico toxicity prediction, followed by in vivo evaluation, quantum description and SAR analysis, network pharmacology, protein target prediction, and molecular docking and binding validation. Metabolomics profiling using an augmented computational pipeline revealed BTMR1030, BTMR0052, BTMR1070, and BTMR1071 as potential metabolites of berberine. Further toxicity assessment of berberine and its metabolites revealed BTMR0052 is the most detrimental metabolic intermediate with the highest toxicity score. Interactome prediction and docking studies revealed that it can interact with an array of proteins belonging to hydrolases, cytochrome P450, kinases, GPCR, membrane receptors, and so forth. The results predicted mechanistic explanations of toxicity and highlighted potential structural modifications based on SAR that could improve therapeutic potential.