Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl

Area of Science:

• Supramolecular Chemistry
• Medicinal Chemistry
• Analytical Chemistry

Background:

• Cyclodextrins (CDs) exhibit moderate binding affinities for fentanyl (Ka ~ 100-200 M⁻¹).
• Development of effective countermeasures for synthetic opioid exposure necessitates stronger host-guest interactions.

Purpose of the Study:

• Synthesize novel cyclodextrins with enhanced binding capabilities for fentanyl.
• Investigate the binding behavior and affinity of these new CDs for fentanyl hydrochloride.

Main Methods:

• Synthesis of cyclodextrins with thioalkylcarboxyl or thioalkylhydroxyl moieties.
• Equilibrium binding affinity measurements (Ka).
• Nuclear Magnetic Resonance (NMR) spectroscopy (1D ¹H, 2D-ROESY) and molecular dynamics (MD) simulations.

Main Results:

• A novel cyclodextrin derivative achieved a significantly high binding affinity for fentanyl (Ka = 66,500 M⁻¹).
• NMR and MD simulations revealed an unexpected dual-orientation binding mode of fentanyl within the cyclodextrin cavity.
• Strong correlation observed between MD-derived binding energies and NMR-derived affinities.

Conclusions:

• The developed cyclodextrins demonstrate unprecedented affinity for fentanyl, surpassing previous reports.
• The findings support the use of MD simulations as a predictive tool for optimizing cyclodextrin candidates.
• These advanced cyclodextrins show promise for applications in medical countermeasures, biosensing, and forensic science.