Computational and synthetic study reveals potent binding of novel pyridine derivatives to human spermine oxidase, suggesting a channel-plug inhibition mechanism.
Key Points
Synthesize novel 2,4,6-substituted pyridine derivatives and evaluate their electronic properties and binding interactions against human spermine oxidase.
Synthesized three novel 2,4,6-substituted pyridine derivatives via tandem iridium-catalyzed borylation and Suzuki-Miyaura coupling.
Optimized molecular geometries and electronic properties via density functional theory (DFT) at the B3LYP/6-311(d,p) level.
Performed molecular docking simulations against the FAD-binding catalytic domain of the human spermine oxidase crystal structure (PDB ID: 7OXL).
Synthesized pyridine scaffolds demonstrated binding affinities with Vina scores of -8.3 to -9.7 kcal/mol, markedly stronger than the natural substrate spermine (-5.8 kcal/mol).
Structural analysis supported a 'Channel Plug' inhibitory mechanism, wherein bulky heterocyclic cores sterically block access to the FAD catalytic center.
Identified critical catalytic pocket interactions with key residues including Ser463, Gly13, Ala36, Glu35, Leu56, Leu14, Ala15, and Thr465.