Computational DFT and docking investigation of isoproterenol delivery using Al₁₂N₁₂ and Al₁₂O₁₂ inorganic nanocarriers

Abstract The development of efficient nanocarriers for catecholamine drugs remains a critical challenge in cardiovascular therapeutics. This study presents the first comprehensive computational investigation of aluminum-based nanoclusters (Al₁₂N₁₂ and Al₁₂O₁₂) as drug delivery vehicles for Isoproterenol, a synthetic catecholamine used in managing bradycardia, heart block, and cardiac arrest. Using density functional theory (DFT) at the B3LYP/6-311 + G(d) level, the adsorption of Isoproterenol onto these nanoclusters was systematically evaluated through geometric, electronic, and spectroscopic analyses. The calculated binding energies ranged from ‒29 to ‒33 kcal/mol for Isoproterenol/Al₁₂N₁₂ complexes and from ‒61 to ‒88 kcal/mol for Isoproterenol/Al₁₂O₁₂ complexes in gas phase, and ranged from ‒25 to ‒28 kcal/mol for Isoproterenol/Al₁₂N₁₂ complexes and from ‒54 to ‒75 kcal/mol for Isoproterenol/Al₁₂O₁₂ complexes in water phase, suggesting favorable adsorption interactions, with Al₁₂O₁₂ exhibiting stronger interactions due to the higher electronegativity of oxygen. A substantial increase in dipole moment upon complexation suggests which may contribute to improved aqueous solubility and potentially facilitate cellular uptake, favorable attributes for drug delivery applications. Molecular docking against the β₁-adrenergic receptor (β₁AR) revealed that the Isoproterenol/nanocluster complexes achieved docking scores of‒15.98 and ‒16.56 kcal/mol for Al₁₂N₁₂ and Al₁₂O₁₂ complexes, respectively, markedly superior to free Isoproterenol (‒7.41 kcal/mol). Ab initio molecular dynamics (AIMD) simulations at 300 K further supported the thermal and structural stability of the most stable Isoproterenol/Al₁₂N₁₂ and Isoproterenol/Al₁₂O₁₂ complexes under the simulated conditions, with no apparent dissociation or major structural distortion during the 10 ps trajectories. These findings suggest Al₁₂N₁₂ and Al₁₂O₁₂ nanoclusters as promising, previously unexplored carriers for Isoproterenol, offering a foundation for experimental validation and future development of inorganic nanocarrier-based delivery systems for cardiovascular drugs.