Berberine as a Multitarget Therapeutic Agent: Insights from Molecular Docking Studies.

Abstract

Natural compounds are crucial in pharmacological research for modulating numerous biological processes. This is particularly helpful in the case of complex diseases and in overcoming challenges (e.g., drug resistance and adverse effects). Berberine, an isoquinoline alkaloid extracted from plants such as Berberis, Coptis, and Hydrastis species, exhibits a wide range of activities, including antidiabetic, anticancer, anti-inflammatory, antimicrobial, and antiviral. However, due to its low oral bioavailability (poor absorption, high first-pass metabolism, along with rapid elimination), further mechanistic understanding and optimization are required. This review brings together molecular docking data to identify berberine's major targets implicated in various diseases, evaluate its multifunctional therapeutic potential, while exploring the benefits, drawbacks, as well as future research avenues of the methodology. A systematic search of databases, including PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar (as of March 2026), was conducted to identify docking studies providing binding affinity and interaction details. Target scores, Protein Data Bank (PDB) IDs, software/scoring functions (e.g., Auto Dock/Vina, Glide, GOLD, Discovery Studio), and validation methods (e.g., redocking, Root-Mean-Square Deviation (RMSD), and important residues that interact with the target were extracted. Berberine showed good predicted affinities at metabolic targets (between -5.4 and -10.5 kcal/mol) with the highest affinities for AKT1 (3O96; -10.5 kcal/mol) and GLUT4 (-10.1 kcal/mol), which included stabilizing contacts such as GLN79, LYS268, and VAL270 in AKT1 and inflammatory mediators such as TNF-α, TYR103, and TRP107 in GLUT4. Antimicrobial docking studies showed good binding to DNA polymerase III (2POL, -5.32 kcal/mol; GLY219) and FtsZ (8GZY, -6.59; FTSZ), notably FTSZ (3VDB, -38.95 kcal/mol; multiple hydrophobic residues). Anticancer targets included BRAF (1UWJ; -9.53) and exceptionally low energies for Aldose Reductase (ADR) (-48.17 kcal/mol; MM-GBSA), phosphodiesterase 4D (-41.58 kcal/mol), Glucocorticoid Receptor (GR) (-37.08), DHODH (-34.81 kcal/mol), and PDK1 (-31.31 kcal/mol), implicating modulation of the MAPK and PI3K/AKT pathways. Antiinflammatory docking found the top binders to be COX-2 (4COX; -10.16 kcal/mol) and PTGS2 (to -9.0 kcal/mol), while antiviral studies identified SARS-CoV-2 Mpro (6LU7; -9.65 kcal/mol; residues including HIS41, CYS145, and GLU166) and other proteins binding to PLpro, RNAdependent RNA polymerase (RdRp), Spike, alongside Dengue proteins. Multitarget complex formation is promoted by recurring hydrogen bonding, hydrophobic, electrostatic, and π-π interactions, all of which are consistent with the planar, positively charged tetracyclic scaffold of berberine (C20H18NO4 +, 336.38 g/mol). There is methodological variation in docking protocols across studies, and the concordance between scores and activities remains inconsistent; however, datasets with identical parameters remain comparable. Overall, docking evidence reveals berberine to be a multitarget, broad-spectrum lead molecule and further supports the necessity of validating the molecule through molecular dynamics studies, experimental trials, clinical trials, and by designing derivatives, using nanotechnology for delivery, with artificial intelligence optimization, and in combination with other drugs to overcome its pharmacokinetic limitations and transform computational results into therapeutic potential.