A theoretical study of supramolecular chemotherapy with CB[7] and CP[6]: Electrostatic-driven displacement of platinum-based drug.

Supramolecular host-guest systems have gained relevance as platforms for controlled drug release. In this study, we conducted a theoretical comparison between two macrocyclic hosts, cucurbit [7]uril (CB [7]) and carboxylated pillar [6]arene (CP [6]), used as potential drug carriers for platinum-based anticancer agents, focusing on their release triggered by the polyamine biomarker spermine. The energetic and structural features of these systems were analyzed using dispersion-corrected density functional theory (DFT-D3). Binding free energies were also estimated to evaluate the thermodynamic stability of the host-guest complexes. Energy decomposition analysis (EDA) was subsequently employed to gain insight into the interactional driving forces governing the complexes. We also explored noncovalent interaction (NCI) plots to identify regions governed by electrostatic and van der Waals forces. Our results showed that the electrostatic interactions between CP [6] and spermine are significantly stronger than those in the CB [7]-spermine system, reflecting a marked electronic preference for the polyamine that is consistent with the observed spermine-driven drug displacement. Consistently, the calculated binding free energies reveal a clear thermodynamic preference of spermine over oxaliplatin for both macrocycles. Overall, this study sheds light on the energetic landscape of molecular recognition and competitive binding processes in macrocyclic host-guest chemistry, positioning CP [6] as a promising supramolecular carrier for biomarker-mediated drug delivery.