۳-Amino-۵-alkyl/aryl-۱,۲,۴-oxadiazole derivatives for COX-۱, COX-۲, Keap۱ and trypsin protein binding towards oxidative stress and inflammation prevention: In silico investigation

Heterocyclic compounds play a pivotal role in drug discovery, with the ۱,۲,۴-oxadiazole scaffold recognized for its versatility as a bioisostere and broad therapeutic potential. Despite its significance, the subclass of ۳-amino-۵-aryl/alkyl-۱,۲,۴-oxadiazole derivatives remain underexplored. This study employed in silico approaches to evaluate ۱۵۰ compounds of this oxadiazole derivative for their potential to mitigate inflammation and oxidative stress by targeting four proteins implicated in oxidative stress-related and inflammatory pathways: COX-۱, COX-۲, Keap۱, and Trypsin. Molecular docking using AutoDock Vina ۱.۱.۲ identified the top five ligands per protein based on binding affinity, yielding ۱۶ promising candidates. These compounds exhibited favorable interactions with key active-site residues and displayed stronger binding affinities than known antagonists, suggesting potential inhibitory activity. Notably, COX-۲ ligands showed interactions indicative of isoform selectivity. SwissADME analysis revealed that only one compound (ODA۱۴۶) violated Lipinski’s Rule of Five, while BOILED-Egg analysis indicated limited gastrointestinal absorption for most ligands. Toxicity predictions using OSIRIS Explorer flagged three compounds for potential risks due to high-risk substructures. Molecular dynamics simulation within a ۵۰-ns timeframe confirmed the stability of the protein–ligand complexes, with consistent RMSD, RMSF, Rg, and interaction energy values, however, longer simulations would be necessary to capture extended conformational dynamics and provide a more thorough evaluation of complex stability. Collectively, these findings suggest that selected ۳-amino-۵-aryl-۱,۲,۴-oxadiazole derivatives possess potential as inflammation and oxidative stress inhibitors and warrant further experimental validation to confirm their therapeutic viability.

کلیدواژه ها:

oxadiazole ، Inflammation ، oxidative stress ، Molecular docking ، Molecular Dynamics