An Evaluation of the Interaction of Brefeldin A with Mitogen-Activated Protein Kinase (MAPK) and Protein Kinase C (PrKC1): Insights from Inverse Docking and Molecular Dynamics Simulation

Aberrant protein glycosylation is a key driver of colorectal cancer (CRC) progression, contributing to tumour growth, metastasis, and immune evasion. In this study, computational approaches were employed to explore the potential of Brefeldin A (BFA) as an inhibitor of two glycosylation-associated regulatory proteins: Protein Kinase C (PrKC1) and Mitogen-Activated Protein Kinase (MAPK). Molecular docking and structural analysis revealed that BFA binds stably and specifically to the active sites of both proteins, suggesting its ability to modulate their function. Detailed interaction profiling identified key active site residues involved in hydrogen bonding, hydrophobic interactions, and van der Waals forces—further supporting the structural compatibility and specificity of BFA for these targets. The optimal binding poses observed indicate potential allosteric or competitive inhibition mechanisms, which could disrupt critical signaling pathways linked to glycosylation and tumour progression. In addition, Binding free energy estimations indicated strong interactions, with BFA-MAPK and BFA-PrKC1 complexes yielding favorable binding affinities of -22.18 ± 4.50 kcal/mol and -23.90 ± 5.36 kcal/mol, respectively. These values highlight the thermodynamic stability of the complexes and suggest a high likelihood of inhibitory activity under physiological conditions. Collectively, these findings underscore BFA’s potential as a novel inhibitor targeting glycosylation-related kinases in CRC. This work not only proposes BFA as a promising therapeutic lead but also supports glycosylation inhibition as a strategic avenue for CRC control, with broader implications for drug discovery in glycan-related oncogenic pathways.