Structural insights into the inclusion complexes between clomiphene citrate and β‐cyclodextrin: The mechanism of preferential isomeric selection

Abstract

A major challenge in pharmaceuticals for clinical applications is to alter the solubility, stability, and toxicity of drug molecules in living systems. Cyclodextrins (CDs) have the ability to form host-guest inclusion complexes with pharmaceuticals for further development of new drug formulations. The inclusion complex of clomiphene citrate (CL), a poorly water-soluble drug, with native β-cyclodextrin (β-CD) was characterized by a one and two-dimensional nuclear magnetic resonance (NMR) spectroscopic approach and also by molecular docking techniques. Here we report NMR and a computational approach in preferential isomeric selection of CL, which exists in two stereochemical isomers, enclomiphene citrate (ENC; E isomer) and zuclomiphene citrate (ZNC; Z isomer) with β-CD. β-CD cavity protons, namely, H-3' and H-5', experienced shielding in the presence of CL. The aromatic ring protons of the CL molecule were observed to be deshielded in the presence of β-CD. The stoichiometric ratio of the β-CD:CL inclusion complex was observed by NMR and found to be 1:1. The overall binding constant of β-CD:CL inclusion complexes was based on NMR chemical shifts and was calculated to be 50.21 M . The change in Gibb's free energy (∆G) was calculated to be -9.80 KJ mol . The orientation and structure of the β-CD:CL inclusion complexes are proposed on the basis of NMR and molecular docking studies. 2D H- H ROESY confirmed the involvement of all three aromatic rings of CL in the inclusion complexation with β-CD in the solution, confirming the multiple equilibria between β-CD and CL. Molecular docking and 2D H- H ROESY provide insight into the inclusion complexation of two isomers of CL into the β-CD cavity. A molecular docking technique further provided the different binding affinities of the E and Z isomers of CL with β-CD and confirmed the preference of the Z isomer binding for β-CD:CL inclusion complexes. The study indicates that the formation of a hydrogen bond between -O- of CL and the hydrogen atom of the hydroxyl group of β-CD was the main factor for noncovalent β-CD:CL inclusion complex formation and stabilization in the aqueous phase.

Molecular recognition of flunarizine dihydrochloride and β-cyclodextrin inclusion complex by NMR and computational approaches

“…Three-dimensional coordinates of β-CD (PDB Id: 1DMB) were sourced from http://www.rcsb.org/ while FLN was sourced from the UCSF ZINC database (ZINC19360739) [ 54 ]. Molecular docking of FLN into β-CD cavity was carried out following the methods as reported previously [ 50 ]. The grid centre of docking coordinates were x = − 6.89 Å, y = − 7.65 Å and z = 4.34 Å.…”

“…Further NMR spectroscopy could also offer valuable information on chiral recognition or chiral discrimination or both [ 47 – 49 ]. NMR titration data can be used to determine the stoichiometry and association constant of the host–guest complexes [ 50 – 52 ].…”

“…Two-dimensional (2D) NMR method such as 1 H- 1 H COSY (COrrelation SpectroscopY) is a useful technique, which provides information on the 1 H signals arising from neighbouring protons connected through bonds and protons signals emerging from up to 4 bonds can be captured. Two-dimensional 1 H- 1 H Rotating-frame Overhauser Effect SpectroscopY (ROESY) has been found to be useful for the investigation of the interaction between CD and guest molecule as the Nuclear Overhausser Effect (NOE) cross-peaks are observed between the protons that are close in space even if they are not bonded [ 47 , 50 – 52 ]. Two-dimensional 1 H- 1 H ROESY provides useful information about the location and depth of inclusion of guest molecule into CD cavity [ 47 , 50 – 52 ].…”

The Development of a New Complexation Technique of Hydrocortisone Acetate with 2-Hydroxypropyl-β-Cyclodextrin: Preparation and Characterization

“…1 H Nuclear magnetic resonance ( 1 H-NMR) spectra of the physical mixture and the inclusion complex were dissolved in DMSO-d 6 and analyzed at 400 MHz. Chemical shifts were expressed per million.…”

“…CDs are capable of forming inclusion complexes with various types of organic compounds with improve solubility or other physicochemical properties [3]. Due to the unique truncated cone structure of CDs, it can accommodate hydrophobic guest molecules inside the cavity [6] (Figure 2a). The size and geometry of the molecule to be included in the CD must be adequate for the size and shape of the non-polar cavity.…”