A computational-first proof-of-concept for dual-function metal chelation and aggregate neutralization in an Aβ42...

Alzheimer's disease (AD) pathology is amplified by a self-reinforcing metal-Aβ-ROS axis, in which redox-active Cu and Fe bound to Aβ N-terminal histidines catalyze Fenton-like ROS generation and accelerate aggregation. Existing single-target interventions - anti-amyloid antibodies, antioxidants, metal-protein attenuating compounds, aggregation inhibitors, and photooxygenation catalysts - each address only one node of this loop. We used a computational-first framework to evaluate a dual-function strategy targeting two connected points of the axis: upstream redox-active metal sequestration by maltol, and downstream photodynamic modification of Aβ aggregates via endogenous protoporphyrin IX (PpIX), generated from 5-aminolevulinic acid (5-ALA) under 400 nm illumination. Drosophila experiments served as functional validation, testing whether this combined intervention improved Aβ42-associated behavioral and survival outcomes and was tolerated in wild-type (WT) flies. DFT calculations (B3LYP-D3BJ/def2-SVP//def2-TZVP, CPCM/SMD water) showed deprotonated maltol localizes oxygen-donor electron density comparable to deprotonated deferiprone, and forms a converged, solvent-stabilized Fe(III)-maltol complex. Cu(II) and Zn(II) coordination was weak and geometrically incomplete, indicating an Fe-preferential rather than broadly nonspecific chelation profile; the study does not demonstrate protection against Cu(II)-mediated ROS. Time-dependent DFT predicted PpIX excitations spanning the visible/near-UV range consistent with photosensitizer behavior, and docking against Aβ42 fibril 5OQV showed PpIX engaged the central hydrophobic/turn surface more strongly than chlorin e6 or maltol. In a pan-neuronal Aβ42 Drosophila model, dual treatment improved climbing performance (p = 2.39 × 10^-3 vs. untreated Aβ42) and extended lifespan (log-rank p = 6.04 × 10^-13; median survival ∼40 d); WT + Treatment flies appeared tolerant, though no formal statistical contrast was pre-specified. Treatment-group ThT amyloid burden was not measured, so no amyloid-reduction claim is made. Because chelation-only and 5-ALA/light-only arms were not included, we cannot attribute improvement to either intervention alone and cannot make a formal claim of additive or interactive effects between the two intervention components. The combined intervention was associated with improved behavioral and survival outcomes in the Aβ42 Drosophila model. Because the present study lacks single-intervention controls and treatment-group pathological measurements, these findings do not establish the mechanism responsible for the observed functional improvement. The study illustrates how ground-state, excited-state, and docking calculations can jointly inform a computationally motivated intervention tested in a tractable organismal model.