Investigation of the interactıon between the Smad3-Smad4 heterotrimeric complex and the SB-431542 molecule using the molecular docking method

The binding mechanism between the SB-431542 molecule and the Smad3-Smad4 heterotrimeric protein complex, a key regulatory component of the transforming growth factor beta (TGF-β) signaling pathway. The dysregulation of TGF-β signaling is implicated in various pathological conditions, including cancer and fibrosis. While SB-431542 is known to inhibit TGF-β signaling by targeting the TGF-β R1 receptor, its potential direct or indirect interaction with downstream Smad complexes remains to be clarified. Molecular docking simulations were performed using AutoDock Vina 1.5.7 to investigate the interaction between SB-431542 and the Smad3-Smad4 heterotrimeric complex. The results indicate a high binding affinity of SB-431542 to the complex (−10.6 kcal/mol), mediated through strong hydrogen bonding and hydrophobic interactions with amino acid residues Arg285, Glu288, and Glu337. These interactions suggest a possible mechanism by which SB-431542 may exert additional inhibitory effects on TGF-β signaling downstream of receptor engagement. The findings are relevant for the development of targeted therapeutics aimed at modulating TGF-β signaling in cancer, fibrosis, and other related diseases. The interaction data provide insights that may guide rational drug design and combinatorial therapy strategies. A structure-based pharmacological model predicting SB-431542’s interaction profile with Smad complexes, supporting its repositioning or optimization for extended inhibitory functions in TGF-β-associated pathways. This model can be applied in drug discovery pipelines focused on Smad-dependent signaling disorders, particularly in the contexts of oncology, regenerative medicine, and anti-fibrotic therapies