5‐fluorouracil dimers in aqueous solution: molecular dynamics in water and continuum solvation*

Abstract

ABSTRACT:The interactions established in aqueous solution by a variety of 5-fluorouracil (FU) dimers in water were examined to elucidate the strength of drug-solvent interactions. Molecular dynamics simulations for clusters made up of the FU dimer alone or embedded in 4, 12, and 100 waters at high temperature, followed by simulated annealing, allowed comparing the dimer structures in the different environments, the solute-solvent radial distribution functions and the cluster energetics. The statistics were consistent with those obtained from a 10 ns MD simulation in the NPT ensemble in 385 waters. Interestingly, the F atom was never preferred to O as H-bond acceptor either in the dimer or in water. The interactions within the dimers turned out to be remarkably affected by the presence of the solvent: stacked structures, unfavorable in the gas phase, prevailed even in the presence of four water molecules. The presence of real water molecules is thus of paramount importance to stabilize the system, using molecular dynamics or, alternatively, if affordable, the MP2 level. Geometry optimizations of the clusters at the B3LYP/6-31G * or HF/6-31G * level, in fact, though starting from a stacked hydrated arrangement of the FU dimer, produced almost exactly the same seashell structure. The polarizable continuum model is convenient to compute the solvation free energy of the dimers and clusters at the HF or MP2 level. Also, the partial charge distribution of the clusters can profitably be used to evaluate the solvent effect in the continuum framework.

Spectroscopic and calorimetric studies of formation of the supramolecular complexes of PAMAM G5-NH2 and G5-OH dendrimers with 5-fluorouracil in aqueous solution

“…In water it dissolves better (85.1 mM (Sloan et al, 2005), 96.9 mM (Singh, 2005), 138.2 mM (Szterner, 2008)) than in ethanol (<1 mM, (Kobayashi et al, 1998)). The results of calculation by the method of molecular dynamics (Alagona et al, 2002;Hamad et al, 2006) and ab initio (Del Bone, 1982), made for hydrated 5-fluorouracil, confirm the suggestion by Pauling (1959) about the hydrophobic character of the fluorine substituent. In concentrated solution, 5-fluorouracil forms twomolecular sets, in which one of the possible types of interactions (apart from COÁ Á ÁH) is the interaction of fluorine radicals (FÁ Á ÁF) directed to the cavity formed in the structure of liquid water (Hamad et al, 2006).…”

Interplay of intra‐ and intermolecular H‐bonds for the addition of a water molecule to the neutral and N‐protonated forms of noradrenaline

“…For flexible molecules it is necessary to use model built structures to perform an efficient sampling of the potential energy surface. In the case of a dimer, where either H‐bonding or stacking interactions (or even both) are possible in vacuo, we recently resorted to molecular dynamics simulations in water clusters to determine likely “solvated” structures 37. A supermolecule approach can also be expedient, placing a water molecule in the vicinity of the H‐bond partners and allowing the complex to relax.…”

On Complex Formation between 5-Fluorouracil and β-Cyclodextrin in Solution and in the Solid State: IR Markers and Detection of Short-Lived Complexes by Diffusion NMR

“…The dimensions of both the host and its guest molecule seem to match well: ca. 6.5 Å for both the β-CD cavity [31] and 5-FU [50], allowing one to expect the formation of a 1:1 complex (see the dimensions of the β-CD molecule in Figure 1c). The formation of 5-FU/β-CD inclusion complexes in aqueous solution was indicated by UV spectroscopy, as well as in solid state (physical mixture and kneaded mixture) by powder X-ray diffraction and FT-IR spectroscopy [51].…”