Abstract
Cyclodextrins are well known for their ability to form stable, highly soluble complexes with various substances, which makes them widely used as excipients in food, cosmetics, and pharmaceuticals. In this work, properties of heptakis(2,6-O-dimethyl)-β-cyclodextrin (DM-β-CD) in vacuo and in water, as well as its ability to bind the antidepressant drug mianserin (MIA) in aqueous solution, are investigated computationally. The results are shown to depend strongly on the density functional theory (DFT) applied. The most stable conformers of DM-β-CD found with the B3LYP-GD2 method differ from these indicated by M062X-GD3 and other functionals. According to the latter, two crystal structures, ZULQAY and BOYFOK03, optimized in vacuo and in water, respectively, have the lowest energy. Both the B3LYP-GD2 and M062X-GD3 results show that all tested inclusion and noninclusion complexes of MIA:DM-β-CD in stoichiometry 1:1 are stable in water. However, the structures and their energetic properties obtained with each method differ: in the most stable configurations, different aromatic rings of MIA are embedded inside DM-β-CD, and the corresponding complexation energies (calculated with the 6-31++G(d,p) basis set and corrected for the basis set superposition error) are −29.6 (B3LYP-GD2) and −23.9 (M062X-GD3) kcal/mol. The NMR spectra of DM-β-CD and MIA:DM-β-CD are also compared.
Highlights
Cyclodextrins (CDs) are cyclic oligosaccharides, which, due to their toroidal shape and ability to form stable, water-soluble inclusion complexes with various organic molecules, in the last decades found many applications in chemistry, cosmetic and food industry, as well as in pharmacy and medicine.[1−9] The solubility of natural cyclodextrins (α, β, and γ-CDs) in water at the room temperature is not very high (145, 18.5, and 232 mg/ mL, respectively) and among them, β-CD seems to be the worst candidate for a drug carrier
The conformational flexibility of native cyclodextrins as well as of the inclusion complex 1:1 of β-CD with phenylalanine was analyzed using the simulation techniques.[67−69] According to the results reported by Jana and Bandyopadhyay, upon complexation, the flexibility of both molecules, β-CD and zPHE, is significantly reduced, so their conformational fluctuations in the complex are much more limited than in the free molecules.[69]
An attempt was made to find and characterize the lowest energy structures of DM-β-CD and its complex with mianserin using a computational approach, in which the configuration space was explored by successively increasing the accuracy of the applied method up to the density functional theory (DFT) level
Summary
Cyclodextrins (CDs) are cyclic oligosaccharides, which, due to their toroidal shape and ability to form stable, water-soluble inclusion complexes with various organic molecules, in the last decades found many applications in chemistry, cosmetic and food industry, as well as in pharmacy and medicine.[1−9] The solubility of natural cyclodextrins (α-, β-, and γ-CDs) in water at the room temperature is not very high (145, 18.5, and 232 mg/ mL, respectively) and among them, β-CD seems to be the worst candidate for a drug carrier. Its solubility in water is 570 mg/mL, so it is about 30 times greater than that of β-CD, while the diameter of its cavity is practically the same as in the native cyclodextrin.[8]. Despite these undoubted advantages and a wide range of possible practical applications, knowledge about this molecule is quite limited. The structure and other properties of DM-β-CD in crystals are determined by interactions with similar molecules, while its characteristics in the gas or liquid phase can be very different and have a large influence on its chemical behavior, but they were not explored in the past. There are some other theoretical studies concerning the DM-β-CD molecule, but they mostly focus on its inclusion complexes, in which the host geometry is Received: August 2, 2021 Revised: October 24, 2021 Published: November 24, 2021
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