Wilson's disease is a potentially fatal metabolic disorder characterized by the toxic accumulation of copper in the liver and brain. Current pharmacological treatments rely on structurally flexible chelating agents that lack architectural preorganization. This flexibility impairs metal-ion selectivity, frequently leading to the unintended and harmful depletion of essential zinc. To address this structural limitation, this study utilizes a rigid-body computational docking engine based on the Hard–Soft Acid–Base (HSAB) principle to evaluate macrocyclic architectures for optimal copper selectivity. The computational screening identified a specific dithiadiazacyclododecane diacetic acid derivative that entirely bypasses the geometric coordination penalties typical of symmetric macrocycles. This optimal architecture achieves an unprecedented theoretical coordination score for copper and superior selectivity against zinc. Furthermore, pharmacokinetic modeling predicts: Optimal aqueous solubility High oral absorption Inability to cross the blood-brain barrier These combined thermodynamic and pharmacological properties establish this preorganized macrocycle as a highly promising therapeutic candidate for advanced preclinical development in Wilson's disease.
Andrés Sebastián Pirolo (Sat,) studied this question.