Chromenopyridine Derivatives as Novel 6PGD Inhibitors, MD Simulation, and Antioxidant Capacities

This study investigated the inhibitory effects of chromeno[4,3‐b]pyridine‐benzisoxazole derivatives on 6‐phosphogluconate dehydrogenase (6PGD), an important target enzyme in cancer treatment. In vitro analyses determined K i values of 1.77 μM and 2.21 μM for Compounds 1 and 2, respectively. Complementary in silico studies revealed that Compound 1 exhibited the strongest inhibitory activity, with a calculated binding free energy of −10.27 kcal/mol. Molecular dynamics simulations (100 ns) confirmed the structural stability of the enzyme–ligand complex, and free energy surface analysis showed a single dominant thermodynamic equilibrium state reflecting high conformational stability. MM/PBSA binding free energy calculations yielded a total energy of −26.78 ± 0.62 kJ/mol, indicating that the interaction is primarily stabilized by van der Waals and electrostatic forces. Additionally, antioxidant tests conducted using 10 different methods showed that chromeno[4,3‐b]pyridine‐benzisoxazole derivatives have better antioxidant capacity compared to reference anticancer drugs. When these findings are considered together, it appears that chromeno[4,3‐b]pyridine‐benzisoxazole derivatives are effective, stable, and promising 6PGD inhibitors.