Computational discovery of marine natural phytochemicals as novel SIRT7 inhibitors for cancer treatment

With cancer causing over 10 million deaths annually, identifying novel therapeutic targets is crucial. SIRT7 is a NAD-dependent deacetylase that regulates oncogenic pathways, making it a promising therapeutic target. However, no approved medications currently exist against SIRT7, and available inhibitors exhibit limited efficacy alongside significant toxicity. Therefore, this study explores marine biodiversity as a source of SIRT7 inhibitors. Molecular docking screening of SIRT7 identified four promising marine phytochemicals (CMNPD28383, CMNPD24305, CMNPD24304, CMNPD14924) with superior binding affinities (-9.9 to -8.4 kcal/mol). Molecular dynamics simulations confirmed stable protein-ligand complexes with RMSD variations of 4.714 to 6.905 Å. Most of these phytochemicals demonstrated favorable ADMET profiles, high oral bioavailability, strong predicted anticancer activity (Pa > 0,6), and potent machine learning (RandomForest Cross Validation R² = 0.8614 ± 0.0244) predicted inhibitory activity (pIC₅₀: -2.110 to -2.875; IC₅₀: 129 nM to 749 nM). Therefore, these marine phytochemicals could be potential novel SIRT7 inhibitors with excellent drug-like properties, providing a foundation for further experimental validation and potential clinical translation. In addition, these computational approaches offer a promising avenue to develop safer and effective cancer therapeutics from marine sources.