Comparison of Three Molecular Simulation Approaches for Cyclodextrin‐Ibuprofen Complexation

Abstract

Cyclodextrins are widely used for the solubilisation of poorly soluble drugs in the formulations. However, current cyclodextrin formulation development strongly depends on trial-and-error in the laboratory, which is time-consuming and high cost. The aim of this research was to compare three modeling approaches (Docking, molecular dynamics (MD), and quantum mechanics (QM)) for cyclodextrin/drug complexation. Ibuprofen was used as a model drug. Binding free energy from three simulation methods was calculated as an important parameter to compare with the experimental results. Docking results from AutoDock Vina program showed that the scoring of complexation capability between ibuprofen and cyclodextrins is alpha (α), gamma (γ), beta (β), and HP-beta-cyclodextrins, which indicated similar ranking with the results from phase, solubility diagram experiments. MD simulation indicated that ibuprofen could form the stable complexes withβ-,γ-, and HP-β-cyclodextrins, but not for alpha cyclodextrin. Binding free energies from the MD simulation forβ-,γ-, and HP-β-cyclodextrins were −3.67, −0.67, and −3.87 kcal/mol, individually. The enthalpies of QM simulation forβ-,γ-, and HP-β-cyclodextrins were −17.22, −14.75, and −20.28 kcal/mol, respectively. Results from all three modeling approaches showed similar ranking between ibuprofen and four cyclodextrin molecules as the experimental data. However, MD simulation with entropy calculation had the closest value to experimental data forβand HP-beta-cyclodextrins. Thus, MD simulation with MM-PBSA method may be fit toin silicoscreen for cyclodextrin formulations.

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

“…According to the published thermodynamic effect of complexation in the studies of CA-HPβCD (Ks = 382.7 M −1 ) [7] and CA-βCD (Ks = 339.7 M −1 ) [8], the predicted ranks 1 and 3, respectively, remain in agreement with experimental results. In the literature, good agreement of in silico predictions with experimental results was observed for Ibuprofen systems with β−, γ−, and HPβCD, where dG of binding was simulated with the MM-PBSA approach [30]. The study revealed the most energetically favored Ibuprofen-HPβCD system, the theoretical results were confirmed experimentally.…”

Physicochemical Characterization, Molecular Docking, and In Vitro Dissolution of Glimepiride–Captisol Inclusion Complexes

“…The output of the command and topol.top file suggested that the zero counter ion was added to the system, as previously reported. 38 Each molecular dynamic production run was carried out for 100 ns for each complex. Each recording interval was set to 100 ps for the trajectory and 1.2 ps for the energy.…”

Recent Developments and Applications of the MMPBSA Method

“…A binding interaction was analyzed to show that electrostatic interactions have the largest contribution to the stability of the cucurbituril-pseudorotaxane complex (Malhis et al, 2015 ). Complex stability was analyzed for multiple systems, such as the 1:1 and 1:2 inclusion complexes formed by nor- Seco -cucurbit[10]uril and 1-adamantanmethylammonium in water (El-Barghouthi et al, 2015 ), cyclodextrin-Ibuprofen complexes (Wang R. M. et al, 2015 ), E-selectin-oligosaccharide complexes (Barra et al, 2017 ), and the naringenin-2,6-dimethyl β-cyclodextrin inclusion complex (Sangpheak et al, 2014 ). Finally, enantiomeric discrimination of chiral organic salts by chiral aza-15-crown-5 ether with C1 symmetry was reported (Kocakaya et al, 2015 ).…”