DFT and molecular docking investigation of tamoxifen interactions with metal-encapsulated boron nitride nanocages

Abstract Tamoxifen (TMF), a lipid-soluble selective estrogen receptor modulator (SERM), is extensively used in the treatment of breast cancer. In this work, we systematically investigate the covalent and non-covalent interactions of TMF with the perfect B 12 N 12 compared to as well as with calcium- and potassium-encapsulated derivatives (B 12 CaN 12 and B 12 KN 12 ). These interactions are predominantly mediated by the dimethylamino group (-N(CH₃)₂) of TMF and were examined using density functional theory (DFT) calculations at the M06-2X level, incorporating D3 dispersion corrections (M06-2X-D3) and the 6–31 + G** basis set. The results reveal that TMF undergoes strong chemisorption on B 12 KN 12 (-2.27 eV) and B 12 CaN 12 (-1.91 eV), in contrast to weaker adsorption on the pristine B 12 N 12 surface (-1.75 eV). The strong binding of TMF to B₁₂N₁₂ via its dimethylamino group occurs through a synergistic combination of covalent interactions and hydrogen bonding, accompanied by a larger charge transfer from the drug to the cage, leading to a significant increase in dipole moment and a change in the energy gap. Thermodynamic analyses based on Gibbs free energy and enthalpy changes confirm that complex formation is highly stable, spontaneous, and exothermic. Notably, B 12 N 12 exhibits the shortest recovery time, indicating rapid TMF detachment, whereas B 12 CaN 12 and B 12 KN 12 show longer desorption times, favoring sustained release. ADMET predictions suggest moderate intestinal absorption and good membrane permeability, indicating potential for oral bioavailability. Docking studies reveal that B 12 KN 12 enhances TMF binding to EGFR, HER2, and Caspase-8, despite a minor reduction in ERα affinity, supporting the potential of B 12 KN 12 as a nanocarrier for HER2-driven breast cancer treatment.