A DFT/TD-DFT investigation of clozapine adsorption on B(12)Y(12) (Y = N, P) nanocages as vehicles for applications in schizophrenia treatment.

Clozapine (Clo) is a highly effective antipsychotic for treatment-resistant schizophrenia, but its clinical use is hampered by poor delivery due to its lipophilic nature. In this study, density functional theory (DFT) and time-dependent DFT (TD-DFT) were used to investigate B(12)N(12) and B(12)P(12) nanocages as potential carriers for Clo delivery. Molecular electrostatic potential (MEP) analysis revealed three electron-rich adsorption sites on Clo (N13, Cl16, and N32), which served as anchoring points for nanocage attachment. Clo/B(12)N(12) configurations (A-C) and Clo/B(12)P(12) complexes (D-F) were labelled as Sites 1-3. The findings reveal that the adsorption energies for Clo on both nanocages fall between -20 and -40 kcal mol(-1) (i.e. -39.96 to -22.05 kcal mol(-1)), indicating strong and stable chemisorption. These interactions are both spontaneous and exothermic, as supported by negative values of ΔG (ad) and ΔH (ad). NBO analysis demonstrates greater charge transfer from Clo to B(12)N(12) (up to 1.240e) compared to B(12)P(12) (up to 0.589e). Both nanocages significantly reduce the HOMO-LUMO gap of the system (by 42.66% for B(12)N(12) and 29.52% for B(12)P(12)), which enhances conductivity and could facilitate drug detection. QTAIM analysis indicates that complexes A, C, D and F feature partially covalent interactions, while B and E are more ionic, suggesting a balance between strong binding and the potential for controlled release. Recovery time calculations further show that complexes B and E allow for faster drug release. Overall, these findings highlight B(12)N(12) and B(12)P(12) nanocages as promising nanocarriers for targeted clozapine delivery, combining stable binding with the potential for efficient and controlled drug release and, however, warranting experimental validation for addressing current challenges in schizophrenia therapy.