Inclusion Complexes Between β‐cyclodextrin and the Anticancer Drug 5‐Fluorouracil for its Solubilization: a Molecular Dynamics Study at Different Stoichiometries

Abstract

Cyclodextrins (CDs) are natural macrocyclic oligosaccharides able to solubilize hydrophobic drugs in water improving their bioavailability, thanks to favorable noncovalent interactions particularly in their hydrophobic cavity. Using a simulation protocol proposed in previous work, in this theoretical study based on Molecular Mechanics (MM) and Molecular Dynamics (MD) methods, inclusion complexes between β‐cyclodextrin and 5‐Fluorouracil (5‐FU) are investigated. 5‐FU is an anticancer drug hardly soluble in water used for more than 50 years. This drug is mainly administered by intravenous injection for the treatment of inner cancers or as a cream in the case of skin‐related cancers. For drug delivery applications, it is important to characterize stable inclusion complexes at different drug concentrations in order to enhance the anticancer activity by maintaining lower dose, thus reducing cytotoxic effects on the normal cells, causing several negative impacts in the course of treatment. In this work, the structure and stability of the host–guest complexes β‐CD:5‐FU in a 1:1 and 1:2 stoichiometries are investigated because this drug is relatively small compared to the size of the hydrophobic β‐CD cavity. The 5‐FU complexes with CDs allow its solubilization, thanks to favorable van der Waals interactions. Interestingly, these intermolecular interactions in inclusion complexes may also affect the release profile. MD simulations are a powerful tool to evaluate interactions between hydrophobic anticancer drugs and hydrophilic carriers with an inner hydrophobic cavity such as CDs and oligosaccharides in general.

Different Drug Mobilities in Hydrophobic Cavities of Host–Guest Complexes between β-Cyclodextrin and 5-Fluorouracil at Different Stoichiometries: A Molecular Dynamics Study in Water

“…After the initial energy minimizations, the MD runs, which lasted for 2 ns, at 300 K, analyzing all configurations assumed by the system saved every 5 ps during MD runs, and the optimizations of the final geometries assumed by the systems when an equilibrium state was achieved, the drug inclusion process occurred across both rims (see the animations of the four MD runs provided in the SI, Video S2). Interestingly, the more populated inclusion geometries are very similar to two different arrangements that were found in a previous study performed using the distance-dependent dielectric constant of water (see Figure 2 in Reference [78]). In water, the mobility of drugs is greater.…”

“…The broadest peaks at approximately 12.0 Å to 14.0 Å are due to the second, less-ordered shell of the water molecules around the outer β-CD surface. These are typical hydration shells that recall those already calculated for the native β-CD studied separately in water, as well as, in general, around hydrophilic material surfaces [78,79,90]. Interestingly, the oxygen in the water molecules also displayed a high probability density of being close to the β-CD c.o.m., from 1.17 Å to approximately 3.50 Å, and a second-highest probability density from 3.50 Å to 6.50 Å considering the first and the second MD run performed.…”

Hybrid Organic–Inorganic Biomaterials as Drug Delivery Systems: A Molecular Dynamics Study of Quercetin Adsorption on Amorphous Silica Surfaces

“…The dispersion of the hydrophobic curcumin, an important anticancer drug, has been theoretically studied, both in new pH-dependent carriers proposed by professors Ferruti and Ranucci [96] and well dispersed in nano aggregates formed by amphiphilic cyclodextrins proposed by Mazzaglia [97], and was theoretically investigated. All these theoretical results agree with the experimental data [92][93][94][95]. Possible new classes of hydrophobic drug carriers that can adsorb on the chiral DNA structure are currently being studied [99,100].…”

Unveiling the synergy: a combined experimental and theoretical study of β-cyclodextrin with melatonin

“…62–64 For this reason, an equally valid approach involves molecular mechanics-based molecular dynamics (MM/MD), 65–67 which are applied to confirm experimental insights in terms of complexation affinity, 68–70 structural features 71,72 and spectroscopic analysis. 73 Different studies simulated the encapsulation of a guest with several cyclodextrins in various stoichiometric ratios, 74–78 allowing not only conformational investigations but also the study of the system evolution over time. 79–82…”

“…[62][63][64] For this reason, an equally valid approach involves molecular mechanics-based molecular dynamics (MM/MD), [65][66][67] which are applied to confirm experimental insights in terms of complexation affinity, [68][69][70] structural features 71,72 and spectroscopic analysis. 73 Different studies simulated the encapsulation of a guest with several cyclodextrins in various stoichiometric ratios, [74][75][76][77][78] allowing not only conformational investigations but also the study of the system evolution over time. [79][80][81][82] Among the others, the recently developed GFN2-xTB method was shown to be almost as accurate as DFT 83,84 with the cheap computational cost typical of other semi-empirical methods (3-5 orders of magnitude lower than DFT) and successfully applied to host-guest phenomena.…”