Elucidation of the orientation of selected drugs with 2-hydroxylpropyl-β-cyclodextrin using 2D-NMR spectroscopy and molecular modeling

Abstract

This project aims to study the nature of interaction and orientation of selected drugs such as dexamethorphan HBr (DXM), diphenhydramine HCl (DPH), and lidocaine HCl (LDC) inclusion complexes with hydroxyl-propyl ß-cyclodextrin (HP-ß-CD) using ¹HNMR spectroscopy, 2D-NMR ROESY and molecular-modeling techniques. Freeze-drying technique was used to formulate the inclusion complexes between DXM, DPH and LDC with HP-ß-CD (1:1 M ratio) in solid state. Inclusion complex formation was initially characterized by Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. Further characterization of inclusion complexes to determine the interaction of DXM, DPH and LDC with HP-β-CD was performed using the ¹HNMR spectroscopy, 2D-NMR ROESY and molecular modeling techniques. Inclusion complexes of DXM, DPH and LDC with HP-ß-CD were successfully prepared using the freeze-drying technique. Preliminary studies with FT-IR, DSC, XRD and SEM indicated the formation of inclusion complexes of DXM, DPH and LDC with HP-β-CD at 1:1 M ratio. ¹HNMR study showed a change in proton chemical shift upon complexation. 2D-NMR ROESY (two-dimensional) spectroscopy gave an insight into the spatial arrangement between the host and guest atoms. 2D-ROESY experiments further predicted the direction of orientation of guest molecules, indicating the probability that amino moieties of DXM, DPH and LDC are inside the hydrophobic HP-ß-CD cavity. Cross-peaks of inclusion complexes demonstrated intermolecular nuclear Overhauser effects (NOE) between the amino protons in DXM, DPH and LDC and H-atoms of HP-ß-CD. Molecular modeling studies further confirmed the NMR data, providing a structural basis of the individual complex formations. Microsecond time-level molecular dynamics and metadynamics simulations indicate much stronger binding of DXM to HP-ß-CD and more dynamic behavior for DPH and LDC. In particular, LDC can exhibit multiple binding modes, and even spent some time (∼1-2%) out of the carrier, proving the dynamic nature of the complex. To conclude, 2D-NMR and molecular dynamic simulations elucidate the formation of inclusion complexes and intermolecular interactions of DXM, DPH and LDC with HP-ß-CD.

Keywords: 1HNMR spectroscopy; 2D-NMR ROESY; Hydroxyl-propyl ß-cyclodextrin; Metadynamics; Molecular docking; Molecular dynamic simulations; Molecular-modeling technique.