Synthesis, DFT Evaluation, and Docking-Based Assessment of Novel Substituted Pyridine Derivatives against Human Spermine Oxidase

Abstract

This study combines structure-based molecular docking simulations and DFT calculations to investigate interactions between the crystal structure of human Spermine Oxidase (SMOX) and a series of three novel 2,4,6-substituted pyridine compounds as docking-prioritized SMOX-interacting candidates. The synthesis employed tandem iridium-catalyzed borylation and Suzuki-Miyaura coupling. DFT calculations were performed at the B3LYP/6-311(d,p) level to determine the global minimum energy geometries and electronic properties. These optimized structures served as inputs for molecular docking. The interaction potential was simulated using the human SMOX crystal structure (PDB ID: 7OXL). Docking grids were centered on the FAD-binding catalytic domain. The precise coordinates were x = -25, y = 93, and z = 60. These coordinates ensured rigorous active-site definition. The synthesized scaffolds exhibited superior binding affinities with Vina scores ranging from -8.3 to -9.7 kcal/mol. These scores are significantly higher than the natural substrate, spermine (-5.8 kcal/mol). Structural analysis used the FAD cofactor as a landmark, supporting a hypothesized "Channel Plug" mechanism in which the bulky heterocyclic core sterically hinders access to the catalytic center. The results illustrate that the key interacting residues include Ser463, Gly13, Ala36, Glu35, Leu56, Leu14, Ala15, and Thr465. These findings provide a robust theoretical structural rationale for developing site-specific SMOX modulators and prioritize the use of pyridine scaffolds to target polyamine-binding cavities.