A molecular dynamics study of conformations of beta-cyclodextrin and its eight derivatives in four different solvents

Abstract

Understanding the atomic level interactions and the resulting structural characteristics is required for developing beta-cyclodextrin (βCD) derivatives for pharmaceutical and other applications. The effect of four different solvents on the structures of the native βCD and its hydrophilic (methylated βCD; MEβCD and hydroxypropyl βCD; HPβCD) and hydrophobic derivatives (ethylated βCD; ETβCD) were explored using molecular dynamics (MD) simulations and solvation free energy calculations. The native βCD, 2-MEβCD, 6-MEβCD, 2,6-DMβCD, 2,3,6-TMβCD, 6-HPβCD, 2,6-HPβCD and 2,6-ETβCD in non-polar solvents (cyclohexane; CHX and octane; OCT) were stably formed in symmetric cyclic cavity shape through their intramolecular hydrogen bonds. In contrast, βCDs in polar solvents (methanol; MeOH and water; WAT) exhibited large structural changes and fluctuations leading to significant deformations of their cavities. Hydrogen bonding with polar solvents was found to be one of the major contributors to this behavior: solvent-βCD hydrogen bonding strongly competes with intramolecular bonding leading to significant changes in structural stability of βCDs. The exception to this is the hydrophobic 2,6-ETβCD which retained its spherical cavity in all solvents. Based on this, it is proposed that 2,6-ETβCD can act as a sustained release drug carrier.

Metadynamics supports molecular dynamics simulation-based binding affinities of eucalyptol and beta-cyclodextrin inclusion complexes

“…The R g representing the mass weighted scalar length of each atom from the center of mass of the molecule is used to measure the size and shape of a molecule. The parameter A 79,80 describing the averaged cavity area of bCD molecule (assumed as a circle area) is calculated from the distances between bCD's center and the group of atoms of each glucose unit using the following equation:…”

Computer-Aided Design of Cefuroxime Axetil/Cyclodextrin System with Enhanced Solubility and Antimicrobial Activity

“…The eligibility of certain kinds of cyclodextrin to achieve the desired stability of the system in solution is determined by the structure of CD and guest API [13]. The thermodynamic effect described by Gibbs free energy of complex formation, as well as by entailed stability constant Ks, can be estimated by structure-based modeling with in silico methods [11,12,[14][15][16][17][18]. Application of theoretical approaches, considering a vast number of testable cyclodextrin derivatives, is an essential tool for streamlining experimental investigation.…”

Direct and Regioselective Di‐α‐fucosylation on the Secondary Rim of β‐Cyclodextrin

“…[52] In contrastt ow hat is commonly assumed, the cyclodextrin cone is quite flexible, especially in protic solvents. [53] This is apparent from the tumbling of glucoside units,w hich bend outwards and distortt he conical shape and the hydrogen-bondingn etwork. [49] Indeed, our analysisr eveals thats pecifically the fucosylated glucoside units show enhancedr otation andi ncreased chair flexibility.T hese tilted states are not frequent, but are stable over several nanoseconds ( Figure S4).…”

“…Since a recent comprehensive study of native CDs in water showed that structural and dynamic properties may differ depending on the choice of force field, two different force fields, that is, GROMOS 53A6 and Q4MD, were used in combination with the GROMACS simulation package . In contrast to what is commonly assumed, the cyclodextrin cone is quite flexible, especially in protic solvents …”