Theoretical insight and molecular recognition of oxatub[4]arene-based organic macrocycle as a supramolecular host for antipsychotic drug risperidone

[Display omitted] •Hydroxylated Oxatub[4]arene (HTA4) has the potential to create stable supramolecular complexes with Risperidone (RSP).•The formation of two complex conformers of RSP@HTA4 is spontaneous and one of the conformers performs robust stability.•NBO, NCI-RDG, QTAIM, and IGMH analysis characterize the non-covalent interactions of the inclusion complexes.•LOLIPOP and IRI-π analysis perform π-interactions insight that supports the key feature of the macrocycle HTA4. Neurological diseases such as schizophrenia and other psychotic disorders can be treated with one of the second-generation antipsychotic drugs, the aromatic benzisoxazole derivative, namely risperidone (RSP), which is hydrophobic; making it difficult to dissolve effectively into body fluids. Oxatub[4]arene (TA4) is a novel organic macrocycle with a π-electron-rich hydrophobic nanocavity and has previously been reported to form stable host–guest inclusion complexes with several aromatic compounds. This study carried out the theoretical investigation and molecular recognition of four RSP-docked hydroxylated TA4 (HTA4) conformers or RSP@HTA4. All structures were optimized and calculated using B3LYP/def2-SVP level theory with DFT-D4 dispersion correction. Complex conformer RSP@HTA4-III is proven to have the highest stability, least reactivity, and the formation is the most energetically favorable. By reviewing the ΔG value of the inclusion process, it was found that only the complex formation with HTA4-II and HTA4-III hosts was spontaneous. All non-covalent interactions involved and responsible for complex stabilization were described using NBO and NCI-RDG analysis. Further analysis using QTAIM characterized strong interactions within the complexes. In contrast, weak interactions were modeled using IGMH, followed by π-stacking interactions, which were specifically analyzed using LOLIPOP and IRI-π. The results of this pre-experimental study demonstrate and prove the excellent stability of RSP@HTA4. It also provides insight and support in developing an affordable and appropriate drug delivery system for RSP or similar drugs.