Modeling Chelator Substituent Effects as Therapeutic Targets in Neurodegenerative Diseases

We explore disease-modifying therapies (DMTs) that focus on the front-end pathology of widespread neurodegenerative diseases such as Alzheimer's disease (AD). From recent studies, a promising DMT route is chelation therapy, which addresses disease initiation by redox-active biometals within the central nervous system (CNS) that produce reactive oxygen species (ROS) and promote peptide aggregation. This research focuses on density functional theory (DFT) studies of chelator candidates based on tetradentate Schiff bases and investigates the physicochemical properties that contribute to effective therapeutic capabilities. A property of high interest is the chelate selectivity of Cu-(II) vs Zn-(II) vis-à-vis binding to amyloid-β (Aβ) peptides in diseased tissues. Design modifications of chelator candidates allow for the identification of crucial factors in binding affinity, selectivity, etc. This study reveals that electronic factors are much more influential than steric effects across the diverse analogue library. The sensitivity of Cu-(II)/Zn-(II) selectivity to ring substituent effects is significant, specifically through the implementation of complementary electronic pairing between a directing group and a ring moiety directly involved in chelation. Electron-donating substituents on the phenol ring and electron-withdrawing substituents on the pyridine ring enhance the desired Cu-(II)-Schiff base selectivity toward the therapeutic target.