Fermented Bamboo Shoots as a Source of Natural HRAS Inhibitors: An Integrative Metabolomics, Pharmacokinetic, and Molecular Simulation Study for Cancer Therapy

ABSTRACT This study explores the therapeutic potential of metabolites derived from fermented bamboo shoots (FBS) ekung , hirring , and mesu with a focus on their interaction with cancer‐associated protein targets. LC‐MS/MS‐based metabolomic profiling identified 138–161 unique metabolites across FBS samples, with butin consistently upregulated. Reverse docking of 81 metabolites against 21 cancer‐associated proteins revealed that butin exhibited the highest binding affinity with GTPase HRAS (PDB ID: 6ZL3; −9.41 kcal/mol), outperforming the FDA‐approved inhibitor tipifarnib (−7.5 kcal/mol). Protein–ligand interaction analysis showed that butin formed seven hydrogen bonds and π‐stacking, while tipifarnib lacked hydrogen bonding. ADMET profiling indicated butin had superior drug‐likeness (QED: 0.694), favorable permeability, no hERG cardiotoxicity risk, and P‐glycoprotein inhibitory activity. Molecular dynamics (MD) simulations over 200 ns further validated these findings. Butin–HRAS complexes showed greater structural stability (RMSD: 0.339 ± 0.045 nm), lower atomic fluctuations (RMSF: 0.223 ± 0.14 nm), and higher protein compactness (Rg: 1.651 ± 0.032 nm) compared to tipifarnib. Butin also maintained 0–8 stable hydrogen bonds, a consistent binding pose, and a more compact free energy landscape. MM‐PBSA calculations confirmed favorable binding energetics. Overall, butin represents a promising HRAS‐targeted anticancer agent derived from traditional FBS fermentation.