Unveiling the gemcitabine drug complexation with cucurbit[n]urils (n=6-8): A computational analysis

Abstract In this work, the DFT-D3 method was employed to investigate the complex formation capability of gemcitabine drug with host cucurbit[n]uril Q[n] (n = 6,7 and8) molecules. The density functional theory studies demonstrate that the most stable configuration is a fully encapsulated complex. In the gemcitabine@[6] and gemcitabine@[7] encapsulated systems the gemcitabine amino -NH2 and the alcoholic group in the carbohydrate bonds with the carbonyl units of Q[n]. The addition of sodium ions leads to the partial exclusion of the gemcitabine molecule and the sodium atoms lie close to the carbonyl portal of Q[7]. Thermodynamic parameters computed for the complexation process exhibit high negative entropy change implying that the encapsulation process is spontaneous and is an enthalpy-driven process. Frontier molecular orbitals are located mainly on the gemcitabine uracil ring, before and after encapsulation formation, indicating that the encapsulation happens by pure physical adsorption. Quantitative molecular electrostatic potentials demonstrate a shift in charge occurs during the complex formation and is more pronounced in gemcitabine@Q[7]. AIM topological analysis illustrates that these complexes are stabilized by various noncovalent interactions including HBs and C···F interactions. The 2D RDG plots exhibit the presence of strong HBs and weak van der Waals interactions and the presence of steric repulsion. The isosurface NCI diagram shows predominant steric interaction in the gemcitabine@Q[6] complex. The NCI isosurface for gemcitabine encapsulated complexes with Q[7] and Q[8] host displays that the green patches are uniformly distributed in all directions. Finally, EDA results demonstrate Paulis repulsive energy is predominant in the gemcitabine@Q[6] complex, while the orbital and dispersion energies stabilize the gemcitabine@Q[7] complex.