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

This study investigated the inhibitory effects of chromeno4,3‐bpyridine‐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 chromeno4,3‐bpyridine‐benzisoxazole derivatives have better antioxidant capacity compared to reference anticancer drugs. When these findings are considered together, it appears that chromeno4,3‐bpyridine‐benzisoxazole derivatives are effective, stable, and promising 6PGD inhibitors.