Ab Initio Modelling of Competitive Drug-Drug Interactions: 5-Fluorouracil Dimers in the Gas Phase and in Solution.

5-Fluorouracil (FU) is a halogen derivative of the uracil nucleoside widely used for treatment of solid tumors and in combination drug regimens for cancer chemotherapy. In drug delivery by biodegradable poly(ester-ether- ester)s, drug-drug interactions are competitive with respect to the drug-copolymer ones. The potential energy and free energy of association for a variety of FU-FU dimers (either H-bonded or stacked) were therefore studied in the gas phase to shed some light on their absolute and relative strength, because competition between these two kinds of interactions was recently proposed [McCarthy et al. Mol Phys 1997, 91, 513] and examined with a combination of methods [Hobza et al. J Phys Chem A 1998, 102, 6921] for uracil dimers. The effect of the computational level [Hartree-Fock/ second order Møller-Plesset (HF/MP2) or B3LYP, including or not counterpoise corrections to the basis set superposition error] was examined as well as that of the use of polarization functions more diffuse than usual 6-31G*(0.25) more diffuse than usual. The MP2 level is necessary to describe stacking interactions, because B3LYP is inadequate for them, giving results very similar to the HF ones. The 6-31G*(0.25) basis set produces very favorable interaction energies, but it is prone to basis set superposition error (BSSE). The binding free energy is noticeably less favorable than the potential energy, due to the increase in vibrational entropy for the association process. There is a good linear relationship between S(vib) and the binding energy for the HF/6-31G* optimized structures. Estimates of the incidence of thermal corrections at the MP2 level were carried out on the MP2/3-21G and B3LYP/6-31G* structures, where possible. The solvation properties in chloroform or in water of the dimers kept rigid at their in vacuo geometries were examined in the polarizable continuum model framework.