Charge-controlled binding, alloy synergy, and the copper anomaly in Au–Ag–Cu dimers to clusters: DFT-derived design rules for targeted drug delivery

New Journal of Chemistry. 2026. Vol. 50. P. 13931–13957.

Novikov A.

The rational design of coinage metal nanocarriers requires a mechanistic understanding of metal-drug binding and predictive descriptors that translate molecular interactions into design rules. Using DFT (B3LYP-D3BJ/def2-TZVP, SMD water), we systematically investigated the binding of 5-fluorouracil (5-FU) and levodopa (l-DOPA) to neutral and cationic homo- and heteronuclear dimers of Au, Ag, and Cu (Au2, Ag2, Cu2, Au–Ag, Au–Cu, Ag–Cu). Cationic dimers bind both drugs substantially more strongly than neutral species, driven by enhanced electrophilicity (ω up to 28 eV), narrower HOMO–LUMO gaps, and amplified electrostatic and orbital contributions identified by energy decomposition analysis (EDA). For oxygen-rich levodopa, copper-bound heterodimers (Cu–Au, Cu–Ag) are strongly favoured (ΔGbind down to −38.9 kcal mol−1) despite modest net charge transfer (Δe− ≈ 0.24 e), revealing a “copper anomaly” where substantial covalent donor–acceptor interactions complement the dominant electrostatic attraction. The alloy enhancement factor (AEF) quantifies synergy: Cu–Au (copper-bound) is strongly synergistic (AEF down to −6.4 kcal mol−1), whereas Au–Cu is anti-synergistic. EDA-NOCV shows that orbital/electrostatic ratios and NOCV localisation provide transferable descriptors, validated by cross-scale calculations on Au6/Au10-based alloy clusters. Orthogonal release pathways are demonstrated: pH (O2 protonation of 5-FU, ΔΔG up to +16.9 kcal mol−1), oxidation (catechol → quinone of levodopa, ΔΔG up to +13.4 kcal mol−1), and thiol competition (ΔGproxy down to −70.7 kcal mol−1). A heuristic Goldilocks binding window (−25 to −40 kcal mol−1) is proposed for levodopa; 5-FU relies more on trigger efficiency. Top candidates for both 5-fluorouracil and levodopa delivery are Au+2 and Cu–Au+. These results establish testable design principles: cationic surfaces, strategic copper placement, alloy synergy, descriptor-based cross-scale validation, and orthogonal release mechanisms for next-generation drug-delivery platforms.

Keywords: химия, chemistry

Publication based on the results of: Металлизированные фталоцианины как высокоэффективные фотосенсибилизаторы в фототерапии рака (2027)