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

Abstract

In this work, we have investigated the complex formation capability of gemcitabine drug with host cucurbit[n]urils, Q[n] (n = 6, 7, and 8) using density functional theory (DFT). The DFT studies demonstrate that the most stable configuration is a fully encapsulated complex. In the encapsulated gemcitabine@Q[6] and gemcitabine@Q[7] complexes, the gemcitabine amino -NH2 and the alcoholic groups bond 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 Gibbs free energy 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, indicating that the encapsulation occurs by pure physical adsorption. Quantitative molecular electrostatic potentials demonstrate a shift in electron density during the complex formation and are more pronounced in gemcitabine@Q[7]. Atoms-in-molecule (AIM) topological analysis illustrate that these complexes are stabilized by various non-covalent interactions including hydrogen bonding (HBs) and C···F interactions. The reduced density gradient (RDG) graph exhibits the presence of strong HBs and weak van der Waals interactions and the presence of steric repulsion. The isosurface non-covalent interactions (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 Pauling’s repulsive energy is predominant in gemcitabine@Q[6] complex, while the orbital and dispersion energies stabilize the gemcitabine@Q[7] complex.