Temozolomide binding to Cucurbit[7]uril: QTAIM, NCI-RDG and NBO analyses

The inclusion behavior of antineoplastic Temozolomide (TMZ) in the cavitand host Cucurbit[7]uril (CB[7]), with 1:1 stoichiometry, was investigated in this research work. Structural and electronic studies were conducted in vacuum and water. We used the DFT/B3LYP and the dispersion corrected DFT-D/wB97X-D functionals with 6-31G(d), 6-31 + G(d) and 6-31 + G(d,p) basis sets. All methods agree on the 3D optimum structure, in which a total inclusion of TMZ in CB[7] cavity is observed. A destabilizing effect of solvation was highlighted and confirmed from Frontier Molecular Orbital and global reactivity descriptors analyses. Furthermore, The nature and strength of intermolecular interactions were studied using Natural Bond Orbital (NBO) and Quantum Theory of Atoms In Molecule (QTAIM) analyses. Both models corroborate on the overall conclusion revealing that the conventional N-HMIDLINE HORIZONTAL ELLIPSISO and improper C-HMIDLINE HORIZONTAL ELLIPSISO H-bonds are mainly the driving forces stabilizing TMZ@CB[7] complex. Also, in the framework of the topological QTAIM analysis, we classified these closed shell interactions and distinguished two kinds of H-bonds: with electrostatic character or partially covalent in nature. The analysis of Espinosa energies unveils a good correlation with the intermolecular bond distance and electron density. Moreover, The Non-Covalent Interactions Reduced Density Gradient (NCI-RDG) method was used to reveal and distinguish between weak interaction regions; in fact it segregates attractive (H-bonding), dispersive (VdW) and repulsive interactions. Finally, from(1)H NMR and TD-DFT computations, we identified, the interaction sites and the electronic transitions responsible of UV-Vis absorption bands, respectively. The best reproduction of experimental spectra is achieved with the dispersion corrected wB97X-D and extended basis sets.

Automated summary

The research investigates the inclusion behavior of the antineoplastic drug TMZ in the CB[7] host, revealing the driving forces stabilizing the TMZ@CB[7] complex and the nature and strength of intermolecular interactions. The analysis also distinguishes two kinds of H-bonds and reveals a good correlation with intermolecular bond distance and electron density through Espinosa energies. Moreover, the NCI-RDG method segregates weak interaction regions and identifies interaction sites responsible for UV-Vis absorption bands.