Targeting neuronal precursor cell-expressed developmentally down-regulated 4 (NEDD4) offers a promising strategy for cardiovascular therapies. NEDD4, a ubiquitin ligase enzyme, is crucial in protein degradation and cellular signaling. Earthworms (Lumbricus genus) are noteworthy for their rich biochemical composition and pharmacological properties. This study investigated the interactions between Lumbricus-derived proteins and NEDD4 to identify potential cardiovascular therapeutic candidates. Using advanced computational techniques, including 3D structure modeling, protein-protein docking simulations, 100 ns molecular dynamics (MD) simulations, and Molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) calculations, we assessed the binding affinities and functional impacts of these proteins on NEDD4 activity. The findings indicated that Lumbricus-derived proteins such as Lumbrokinase, heat shock protein, and elongation factor 1 (EF-1)-alpha showed activities similar to standard antagonists in modulating NEDD4. These results aligned with previous studies showing the inhibitory effects of heat shock protein and EF-1 on NEDD4 ubiquitination and ligase activity. Additionally, MM/PBSA calculations revealed favorable binding free energies for these compounds, underscoring their therapeutic potential in cardiovascular diseases. In conclusion, this study highlighted the potential of Lumbricus-derived compounds in cardiovascular disease therapy via the NEDD4 pathway, warranting further biochemical and preclinical validation and exploring broader therapeutic applications.
Key words: Cardiovascular disease, Earthworm, Lumbrokinase, Molecular dynamics simulation, NEDD4, Protein-protein interactions
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