Computational evaluation of berberine derivatives as potential modulators of TGF-β signalling in cancer

In early tumorigenesis, TGF-β acts as a tumour suppressor by inhibiting cell growth and inducing apoptosis, thereby maintaining cellular homeostasis and preventing malignant transformation. During cancer progression, however, TGF-β signalling is hijacked to promote tumour growth, invasion, migration, and immune evasion, contributing to stemness acquisition and drug resistance. This dual role highlights its context-dependent nature and therapeutic relevance in advanced cancers. In the present study, berberine derivatives were designed and evaluated computationally for their interactions with TGF-β receptors. Ligand and protein preparation were followed by molecular docking and molecular dynamics simulations. Docking analyses revealed that all derivatives exhibited improved binding scores compared to the parent berberine molecule, with all berberine derivatives demonstrating the strongest predicted affinity for both TGFβRI and TGFβRII over the parent molecule. Molecular dynamics simulations, assessed through RMSD, RMSF, SASA, Rg, and PCA analyses, confirmed that the receptor-ligand complexes remained stable throughout the trajectories, supporting their potential to modulate TGF-β signalling. These findings suggest that structural modification of berberine may enhance receptor binding and provide a rational framework for further experimental validation. Considering the limited oral bioavailability of berberine, the development of optimised derivative molecules may overcome this drawback and improve therapeutic potential in the management of advanced cancers.

The online version contains supplementary material available at 10.1007/s40203-025-00512-4.