Studio computazionale di complessi di inclusione a base di ciclodestrine e composti farmacologicamente attivi

Cyclodextrins (CDs) are cyclic oligosaccharides containing 6, 7 or 8 glucose monomers, with the shape of a truncated cone, and belong to the family of cage molecules. These compounds have gained importance in the last few decades thanks to their low-cost and environmental-friendly production and to their low level of toxicity for the human body, making them a key ingredient in drugs’ formulation. In particular, CDs are used as drug delivery systems due to their hydrophobic cavity, which enables them to protect poorly available active compounds, mainly preventing their degradation and directing them to the target, thus reducing undesired side effects. In this context, β-cyclodextrin (β-CD) and its substituted derivatives are preferred because of their optimal size to trap small drug-like molecules. Among the various pharmacologically active compounds, melatonin has been chosen as the guest molecule in the present study. It is involved in the circadian cycle, inhibits free radicals and has therapeutic applications for Alzheimer disease, cardiac disease and cancer, according to recent works. However, its employment as an effective standalone drug is limited by several drawbacks, such as poor pharmacokinetics properties, low water solubility, high sensitivity to light and metabolic instability. The aim of this work is to computationally investigate the structure and the stability of β-cyclodextrin and hydroxypropyl-β-cyclodextrin (HP-β-CD) supramolecular complexes with melatonin, in order to elucidate, at an atomistic level, the host/guest interactions, playing a crucial role in the release of the drug over time, and compare the results with experimental data. A conformational search was performed of the above-mentioned inclusion complexes at a quantum-mechanics semiempirical level of theory, to obtain a sampling of structures which were re-optimized at a higher level of theory (Density Functional Theory, various functionals). Calculations were carried out in gas phase but also in implicit and explicit solvent (water), in order to compare computational results, such as vibrational spectra, solubility and energy stability values, with experimental data. The resulting structures showed that melatonin is always bound inside the β-CD cavity (see figure), as expected, both in gas phase, with a binding energy of about 28 kcal/mol, and in water, with a much weaker binding energy of about 21 kcal/mol. These results are in good agreement with experimental data, which show that melatonin is released from CDs in aqueous solution. The HP-β-CD, instead, presents lateral chains folded inside the cavity, so melatonin is found on top or outside the cavity, showing a good affinity also with the hydroxypropyl chains and the glucose ring. The binding energy values are still in a range between 25 and 32 kcal/mol in gas phase, and between 12 and 22 kcal/mol in aqueous medium (very similar to the values obtained for β-CD), suggesting a comparable complexation from the point of view of thermodynamics. Nevertheless, it is experimentally observed that HP-β-CD releases melatonin faster, probably due to different kinetics. It can be inferred that the melatonin molecule bound inside the cavity of β-CD is more hindered with respect to the melatonin adsorbed on top of HP-β-CD, which is more exposed to solvent and free to leave faster the complexation site. To have a better insight on the release mechanism of β-CDs, further work is in progress with curcumin.