Electronic structure and charge transfer in a Cu(II) curcumin-derived cysteine Schiff base metallointercalator: DFT, NBO, and DNA binding study

Curcumin-derived metal complexes have attracted increasing interest as potential non‑platinum anticancer candidates because of their structural versatility, redox activity, and ability to interact with biomolecular targets such as DNA. In this work, a computational investigation was performed on a cysteine-functionalized curcumin-derived Schiff base and its Cu(II) complex, selected from previously reported experimental systems. The study integrates density functional theory (DFT) calculations, frontier molecular orbital analysis, global reactivity descriptors, spin-density distribution, Natural Bond Orbital (NBO) analysis, molecular docking, and ADMET prediction to clarify the effect of Cu(II) coordination on electronic structure, chemical reactivity, DNA-binding behavior, and pharmacokinetic properties. DFT calculations were used to optimize molecular geometries and evaluate electronic and reactivity parameters. Spin-density and NBO analyses indicated electron delocalization within the coordination environment and ligand-to-metal charge-transfer contributions, supporting the role of Cu(II) in modulating the electronic distribution of the Schiff base framework. Molecular docking simulations showed favorable interactions with DNA for both systems, with the Cu(II) complex displaying stronger stabilization through multiple non-covalent interactions. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction further suggested pharmacokinetic profiles consistent with drug-likeness criteria. Overall, the results indicate that Cu(II) coordination significantly influences the electronic structure and may enhance the DNA-binding potential of the cysteine-functionalized curcumin Schiff base, supporting its relevance for the rational design of new DNA-targeting metal-based anticancer candidates.