Abstract: Post-translational modifications (PTMs) regulate protein function, stability, and interaction networks, and are involved in the pathophysiology of diabetes mellitus through modulation of insulin signaling, β-cell function, and glucose metabolism. Aberrant PTMs contribute to insulin resistance, β-cell apoptosis, and metabolic dysregulation. This study applies a computational framework integrating molecular docking, molecular dynamics (MD) simulations, and virtual screening to investigate the structural and functional impact of PTMs on key diabetes-related proteins. Structural models incorporating phosphorylation, acetylation, ubiquitination, SUMOylation, and methylation were generated to assess conformational changes and ligand binding alterations. Proteins such as AKT2, IRS1, FoxO1, and PDX1 were prioritized based on their functional relevance and PTM profiles. Virtual screening of chemical libraries against PTM-modified protein structures, followed by MD simulations and free energy calculations, was conducted to identify small molecules capable of modulating PTM-influenced sites. Binding affinities, conformational stability, and drug-likeness parameters were analyzed to prioritize compounds for further investigation. The results provide a computational basis for targeting PTM-modified proteins in diabetes, supporting future experimental validation and development of PTM-focused therapeutic strategies.
faki et al. (2025) studied this question.