Molecular Basis of Binding and Stability of Curcumin in Diamide-Linked γ-Cyclodextrin Dimers

Abstract

Curcumin is a naturally occurring molecule with medicinal properties that is unstable in water, whose efficacy as a drug can potentially be enhanced by encapsulation inside a host molecule. In this work, the thermodynamics and mechanism of binding of curcumin to succinamide- and urea-linked γ-cyclodextrin (γ-CD) dimers in water are investigated by molecular dynamics simulations. The simulated binding constants of curcumin to succinamide- and urea-linked γ-CD dimers at 310 K are 11.3 × 10(6) M(-1) and 1.6 × 10(6) M(-1), respectively, matching well with previous experimental results of 8.7 × 10(6) M(-1) and 2.0 × 10(6) M(-1). The simulations reveal structural information about the encapsulation of curcumin inside the diamide-linked γ-CD dimers, with distinct qualitative differences observed for the two dimers. In particular, (1) the predominant orientation of curcumin inside the urea-linked γ-CD dimer is perpendicular to that in the succinamide-linked γ-CD dimer; (2) the magnitude of the angle between the planes of the cyclodextrins is larger for the succinamide-linked γ-CD dimer; and (3) curcumin exhibits greater configurational freedom inside the urea-linked γ-CD dimer. A consequence of some of these structural differences is that the dimer interior is more accessible to water in the succinamide-linked γ-CD dimer. These observations explain the higher stability and lower binding constant observed experimentally for curcumin in the urea-linked cyclodextrin γ-CD dimer compared with the succinamide-linked γ-CD dimer. More generally, the results demonstrate how stability and binding strength can be decoupled and thus separately optimized in host-guest systems used for drug delivery.

Femtosecond Transient Absorption Spectroscopy of the Medicinal Agent Curcumin in Diamide Linked γ-Cyclodextrin Dimers

“…56,57 Moreover, a recent computational study has shown the presence of water molecules and diffusive motions of curcumin within the γ-CD cavities of 66γCD 2 su and 66γCD 2 ur. 55 In addition, our previous 2D NOESY 1 H NMR spectroscopic results show the intermolecular alkyl hydrogen-hydrogen interactions between curcumin and the γ-CD moieties of 66γCD 2 su and 66γCD 2 ur. 29 In short, the slow relaxation dynamics of 66γCD 2 su-curcumin and 66γCD 2 ur-curcumin complexes may be derived from fluctuations of the γ-CD moieties, reorientation of constrained water molecules, diffusive motions of curcumin within the γ-CD a The transient absorption kinetics were fitted with the multiexponential function, f(t) = ∑ i = 1 n a i exp(−t/τ i ), where ∑ i = 1 n |a i | = 1, with the minimum number of exponential terms (n).…”

Comparison of Three Molecular Simulation Approaches for Cyclodextrin‐Ibuprofen Complexation

“…Unlike the traditional Amber force fields, general Amber force field (GAFF) is more general for organic chemical [21]. Some recent articles chose GAFF force fields in MD simulation of CDs [22][23][24]. So the GAFF force field was selected in Antechamber module with AM1-BCC charge method for all molecules.…”

Combination of capillary electrophoresis and molecular modeling to study the enantiomer affinity pattern between β‐blockers and anionic cyclodextrin derivatives in a methanolic and water background electrolyte

“…All MD preparations and simulations were performed by AmberTools 15 program . Some recent articles chose general amber force fields in MD simulation for CDs . Hence, the general amber force field with AM1‐BCC charge model was used for all molecules by Antechamber module.…”