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

• Potent SIRT7 inhibitors: CMNPD28383, CMNPD24305, CMNPD24304, CMNPD14924. • Strong binding affinities (−9.9 to −8.4 kcal/mol) and stable dynamics (RMSD: 4.7–6.9 Å). • Glu260 significantly impacts binding, suggesting a key target for drug optimization. • High oral bioavailability and strong predicted anticancer activity (Pa > 0,6). • RandomForest model (R 2 = 0.8533) predicts potent inhibition (IC 50 : 129–749 nM). 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 R 2 = 0.8614 ± 0.0244) predicted inhibitory activity (pIC 50 : −2.110 to −2.875; IC 50 : 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.