# Quantum Chemical Properties of Fluorouracil/XZn11O12 (X = Zn, Cu, Fe, Ni) Nanocomplexes and Interactions with Human Serum Albumin

## TL;DR

This study uses quantum chemistry to explore how fluorouracil interacts with metal-doped ZnO nanoclusters and human serum albumin, identifying a promising candidate for drug delivery in cancer therapy.

## Contribution

The study introduces Ni-doped ZnO nanocomplexes as a novel platform for fluorouracil delivery with enhanced charge transfer and binding to HSA.

## Key findings

- 5-FU@NiZn11O12 has the lowest HOMO-LUMO gap (2.44 eV), indicating enhanced chemical reactivity.
- 5-FU@NiZn11O12 shows favorable binding to HSA with a binding energy of -5.36 kcal/mol.
- Ni-doped ZnO nanocomplexes exhibit strong potential for drug delivery in anticancer therapy.

## Abstract

This research focused on structural, electronic, and interaction properties of fluorouracil (5‐FU) adsorbed on transition metal (TM)‐doped ZnO nanoclusters (XZn11O12, where X = Zn, Cu, Fe, Ni) using density functional theory (DFT) at the B3LYP/LANL2DZ level of calculations in the gas phase. Among the studied nanocomplexes, 5‐FU@NiZn11O12 exhibited the highest dipole moment (8.08 D), indicating strong polarization and potential surface reactivity though it has a less negative adsorption energy (−20.97 kcal/mol) compared to 5‐FU@FeZn11O12 (−35.51 kcal/mol) and 5‐FU@CuZn11O12 (−28.69 kcal/mol). TM doping significantly reduced the highest occupied molecular orbital–lowest unoccupied molecular orbital gap, with 5‐FU@NiZn11O12 showing the lowest value (2.44 eV), followed by 5‐FU@FeZn11O12 (2.53 eV) and 5‐FU@CuZn11O12 (3.18 eV), suggesting enhanced charge transfer and chemical reactivity. The results from molecular electrostatic potential, quantum theory of atoms in molecules, and non–covalent interaction/reduced density gradient analyses were also in favor of Ni‐doped ZnO nanocomplex. Based on the DFT results, 5FU@NiZn11O12 was selected to analyze its interactions with human serum albumin (HSA). From molecular docking of 5‐FU@NiZn11O12, binding energy (−5.36 kcal/mol) and inhibition constant (117.15 μM) exhibited stronger interactions with HSA, so that it acts as a potential candidate of drug delivery system for anticancer therapy. However, these predictive insights require further experimental validation.

Adsorption of fluorouracil (5‐FU) on XZn11O12 (X = Zn, Cu, Fe, Ni) nanoclusters and its interactions with human serum albumin (HSA) have been studied using density functional theory and molecular docking. Reduced HOMO‐LUMO gap of 5‐FU@NiZn11O12 nanocomplex suggests enhanced charge transfer activity. The favorable binding interactions of 5‐FU@NiZn11O12 with HSA exhibit its potential for drug delivery and anticancer therapy. © 2026 WILEY‐VCH GmbH