Calculation of structural and thermodynamic stability of a- and b-cyclodextrin complexes

Host-guest complexes are playing an increasing role in pharmaceutical applications such as drug delivery systems improving the solubility, stability, bioavailability, and decreasing the toxicity of many drugs. Exploring and/or predicting the stability of hostguest systems using atomic interactions and binding thermodynamics data is crucial in drug design. In this study, α-and β-Cyclodextrin (α- and β-CD) were used in open and closed conformations which provided a flexible framework for hosting guest molecules. Thermodynamic stability parameters (binding enthalpy and free energy of binding) of the complexes were estimated based on the calculated complex structures and validated against isothermal titration calorimetry data. Guest molecules were built with Maestro and optimized by Mopac 2016 at the PM7 semi-empirical quantum mechanic level. The structures of host-guest complexes were calculated by molecular docking using Autodock. Following the atomic structure analysis of the complexes, the calculated interaction energy and free energy values were collected, and simple linear regressions were obtained using the data analysis and regression function of Excel. The structural analysis of the docking calculations showed that the amine guests favored a head orientation, while carboxylates preferred the tail orientation in the closed state of the α-CD. These preferable orientations changed in the open conformation, showing the importance of the host conformation on guest binding. Due to the cavity size of β-CD guest molecules favored the intermediate orientations instead of head or tail for both the open and the closed host conformations. Based on the docked complex structures, good correlations were achieved between calculated and experimental enthalpy values. The most influential host-guest orientations were selected by the comparison of structural and thermodynamic analysis results. In summary, molecular docking provides reliable atomic resolution structures and gives good estimates of the stability of CD complexes. The presented protocol is a good predictive tool of host-guest stability in drug delivery applications of CD. Acknowledgment: The work was supported by Bolyai János Research Scholarship of Hungarian Academy of Sciences