Abstract / Summary
Protein glycosylation is one of the most common post-translational modifications and plays an important role in maintaining protein structure and function. Aberrant glycosylation can alter the structural profile of glycoproteins in colorectal cancer (CRC), thereby contributing to tumour cell survival, invasion, and metastasis. Carcinoembryonic antigen (CEA) is a highly glycosylated and well-established CRC biomarker that also contributes to tumor progression, but its structural complexity makes it difficult to target directly. Therefore, targeting the glycosylation machinery that regulates CEA function may offer an alternative therapeutic strategy. Fucosyltransferase 8 (FUT8) is the sole enzyme responsible for α1,6-linked core fucosylation and regulates the function of several glycoproteins, including CEA. Thus, targeting FUT8 may provide an indirect approach to modulating CEA-associated functions. Marine natural products were selected because of their broad structural diversity and potential to provide unique bioactive scaffolds for drug discovery. In the present study, a marine natural product library was screened using an in silico structure-based approach to identify and prioritize candidate FUT8 binders. Structure-based virtual screening, molecular docking, ADMET prediction, molecular dynamics simulations, and MM/PBSA binding energy calculations were employed to evaluate the selected compounds. The prioritized compounds exhibited stable interactions with key residues within the FUT8 binding pocket. Among these, CMNPD23066 demonstrated the most favourable overall dynamic and energetic profile, characterized by low ligand and protein RMSD values and the most favourable predicted MM/PBSA binding energy. Molecular dynamics simulations further supported the structural stability of the protein–ligand complexes based on RMSD, RMSF, radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen-bond analyses. Collectively, these findings highlight FUT8 as a potential therapeutic target in CRC and identify marine-derived small molecules as candidate FUT8 binders warranting further biochemical and cellular validation.