Effect of Dimethyl Sulfoxide on the Binding of 1-Adamantane Carboxylic Acid to β- and γ-Cyclodextrins

Abstract

Most therapeutic targets are proteins whose binding sites are hydrophobic cavities. For this reason, the majority of drugs under development are hydrophobic molecules exhibiting low solubility in water. To tackle this issue, a few percent of cosolvent, such as dimethyl sulfoxide (DMSO), is usually employed to increase drug solubility during the drug screening process. However, the few published studies dealing with the effect of adding DMSO showed that the affinity of hydrophobic ligands is systematically underestimated. To better understand the effect of DMSO, there is a need of studying its effect on a large range of systems. In this work, we used β- and γ-cyclodextrins (made of 6 and 7 α- d -glucopyranoside units, respectively) as models of hydrophobic cavities to investigate the effect of the addition 5% DMSO on the affinity of 1-adamantane carboxylic acid (ADA) to these cyclodextrins. The two systems differ by the size of the cyclodextrin cavity. The evaluation of binding constants was performed using ultrasound velocimetry, nuclear magnetic resonance spectroscopy, and molecular simulations. All techniques show that the presence of 5% DMSO does not significantly modify the affinity of ADA for γ-cyclodextrin, while the affinity is dramatically reduced for β-cyclodextrin. The bias induced by the presence of DMSO is thus more important when the ligand volume better fits the cyclodextrin cavity. Our work also suggests that free energy calculations provide a sound alternative to experimental techniques when dealing with poorly water-soluble drugs.

Insights into Noncovalent Binding Obtained from Molecular Dynamics Simulations

“…While the guest‐water interactions can effectively be assessed by comparing experimental and calculated free energies of hydration, a quantity often used as target in force field optimization , , the host‐water and host‐guest interactions usually rely on parameter transferability arguments and combining rules for cross‐terms. To further localize the most appropriate degrees of freedom for force field refinement, it might be useful to consider quantities such as the osmotic pressure or activity coefficients that may help to improve the balance between the various force field terms , but also to expand the diversity of experimentally studied systems including modifications of the host molecules as well as considering more complex solvent environments .…”

Oleic Acid Based Cyclodextrins for the Development of New Hydrosoluble Amphiphilic Compounds

“…For RAME--CD and HP--CD derivatives ( Table 2, entries 9-12), the variation of CAC are less marked. [25] The spectrum showed also correlation spots between the internal CD protons and the protons of the aliphatic chain (see supporting information). These values indicated that they possessed a good surface activity compared to the native CDs which are not surface active.…”

Additive-free photo-mediated oxidative cyclization of pyridinium acylhydrazones to 1,3,4-oxadiazoles: solid-state conversion in a microporous organic polymer and supramolecular energy-level engineering

“…Compared to a previously study on the binding constant of the bis(pyridinium)-xylylene moiety with CB7, 32 we obtained a relatively lower K value (1.53 ± 0.82 × 10 4 M −1 ), which was presumably due to solvent DMSO; this solvent fits better into the cavity of a hydrophobic binding site than water. 33 To re-evaluate the binding affinity of CB7 to BH1, the data obtained from UV-Vis titration experiments of BH1 versus CB7, monitored at 330, 340, 360, 366, and 378 nm, were fitted according to the 1 : 1 binding isotherm on the website (Fig. S12 † ), 34 which showed a similar binding constant (4.05 × 10 4 M −1 ).…”