Marine Fungi‐Derived Compounds as Promising <i>KRas</i> Localization Blockers: Structural Insights Into PDE6δ Inhibition

Cancer, often driven by genetic mutations like KRas activation, is a leading global cause of mortality. This study identified potential inhibitors of PDE6δ, a key chaperone required for KRas membrane localization, from marine fungi-derived compounds. Through molecular docking, molecular dynamics (MD) simulations, MMGBSA free energy calculations, and free energy landscape (FEL) analyses, three promising compounds were identified: CMNPD29003, CMNPD9449, and CMNPD30443. Among these, CMNPD29003 exhibited the highest stability, with RMSD values stabilizing between 1 and 2 Å during 500-ns MD simulations, reflecting strong and consistent binding. CMNPD9449 showed moderate stability (RMSD 1-3 Å with slight end-phase increases), whereas CMNPD30443 displayed weaker binding, with significant fluctuations (RMSD 2-6 Å). Despite stable binding (RMSD 1.5-2 Å), the control compound violated Lipinski's molecular weight rules and had poor solubility. MMGBSA calculations revealed CMNPD29003 as the most promising candidate, with a binding free energy of -106.35 ± 22.59 kcal/mol, supported by strong van der Waals and non-polar solvation contributions. CMNPD9449 showed a binding energy of -91.78 ± 11.03 kcal/mol, benefiting from favorable electrostatic interactions. FEL analysis confirmed CMNPD29003's consistent low-energy states. These findings suggest CMNPD29003 and CMNPD9449 as promising PDE6δ inhibitors, warranting further experimental validation for KRas-driven cancer therapies.