Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl
Abstract
Abstract Cyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities ( K a ~ 100–200 M -1 ) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their binding affinity towards fentanyl hydrochloride. The optimal CD studied displays a remarkable affinity for the opioid of K a = 66,500 M −1 , the largest value reported for such an inclusion complex to date. One dimensional 1 H Nuclear Magnetic Resonance (NMR) as well as Rotational Frame Overhauser Spectroscopy (2D-ROESY) experiments supported by molecular dynamics (MD) simulations suggest an unexpected binding behavior, with fentanyl able to bind the CD interior in one of two distinct orientations. Binding energies derived from the MD simulations work correlate strongly with NMR-derived affinities highlighting its utility as a predictive tool for CD candidate optimization. The performance of these host molecules portends their utility as platforms for medical countermeasures for opioid exposure, as biosensors, and in other forensic science applications.
- Publication Date:
- Research Org.:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA)
- OSTI Identifier:
- 1958043
- Alternate Identifier(s):
- OSTI ID: 2005082
- Report Number(s):
- LLNL-JRNL-844442
Journal ID: ISSN 2045-2322; 2680; PII: 29662
- Grant/Contract Number:
- 14-ERD-048; AC52-07NA27344
- Resource Type:
- Published Article
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Name: Scientific Reports Journal Volume: 13 Journal Issue: 1; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Citation Formats
Mayer, Brian P., Kennedy, Daniel J., Lau, Edmond Y., and Valdez, Carlos A. Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl. United Kingdom: N. p., 2023.
Web. doi:10.1038/s41598-023-29662-1.
Mayer, Brian P., Kennedy, Daniel J., Lau, Edmond Y., & Valdez, Carlos A. Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl. United Kingdom. https://doi.org/10.1038/s41598-023-29662-1
Mayer, Brian P., Kennedy, Daniel J., Lau, Edmond Y., and Valdez, Carlos A. Wed .
"Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl". United Kingdom. https://doi.org/10.1038/s41598-023-29662-1.
@article{osti_1958043,
title = {Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl},
author = {Mayer, Brian P. and Kennedy, Daniel J. and Lau, Edmond Y. and Valdez, Carlos A.},
abstractNote = {Abstract Cyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities ( K a ~ 100–200 M -1 ) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their binding affinity towards fentanyl hydrochloride. The optimal CD studied displays a remarkable affinity for the opioid of K a = 66,500 M −1 , the largest value reported for such an inclusion complex to date. One dimensional 1 H Nuclear Magnetic Resonance (NMR) as well as Rotational Frame Overhauser Spectroscopy (2D-ROESY) experiments supported by molecular dynamics (MD) simulations suggest an unexpected binding behavior, with fentanyl able to bind the CD interior in one of two distinct orientations. Binding energies derived from the MD simulations work correlate strongly with NMR-derived affinities highlighting its utility as a predictive tool for CD candidate optimization. The performance of these host molecules portends their utility as platforms for medical countermeasures for opioid exposure, as biosensors, and in other forensic science applications.},
doi = {10.1038/s41598-023-29662-1},
journal = {Scientific Reports},
number = 1,
volume = 13,
place = {United Kingdom},
year = {Wed Feb 15 00:00:00 EST 2023},
month = {Wed Feb 15 00:00:00 EST 2023}
}
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Works referenced in this record:
Cyclodextrins and their uses: a review
journal, May 2004
- Del Valle, E. M. Martin
- Process Biochemistry, Vol. 39, Issue 9
NMR spectroscopic investigation of inclusion complexes between cyclodextrins and the neurotoxin tetramethylenedisulfotetramine: Cyclodextrin-TETS inclusion complexes
journal, March 2012
- Mayer, Brian P.; Albo, Rebecca L. F.; Hok, Saphon
- Magnetic Resonance in Chemistry, Vol. 50, Issue 3
Modeling, synthesis and characterization of zinc containing carbonic anhydrase active site mimics
journal, January 2011
- Satcher, J. H.; Baker, S. E.; Kulik, H. J.
- Energy Procedia, Vol. 4
MMPBSA.py : An Efficient Program for End-State Free Energy Calculations
journal, August 2012
- Miller, Bill R.; McGee, T. Dwight; Swails, Jason M.
- Journal of Chemical Theory and Computation, Vol. 8, Issue 9
Cyclodextrin-Derived Host Molecules as Reversal Agents for the Neuromuscular Blocker Rocuronium Bromide: Synthesis and Structure−Activity Relationships
journal, March 2002
- Adam, Julia M.; Bennett, D. Jonathan; Bom, Anton
- Journal of Medicinal Chemistry, Vol. 45, Issue 9
National Institutes of Health (NIH) Executive Meeting Summary: Developing Medical Countermeasures to Rescue Opioid-Induced Respiratory Depression (a Trans-Agency Scientific Meeting)—August 6/7, 2019
journal, December 2019
- Yeung, David T.; Bough, Kristopher J.; Harper, Jill R.
- Journal of Medical Toxicology, Vol. 16, Issue 1
Gas Chromatography-Mass Spectrometry Analysis of Synthetic Opioids Belonging to the Fentanyl Class: A Review
journal, May 2021
- Valdez, Carlos A.
- Critical Reviews in Analytical Chemistry
UV-vis Spectral Analysis of Inclusion Complexes between β -Cyclodextrin and Aromatic/Aliphatic Guest Molecules
journal, June 2008
- Jiang, Huiming; Xu, Yingmei; Na, Liyan
- Current Drug Discovery Technologies, Vol. 5, Issue 2
Fully Symmetric Cyclodextrin Polycarboxylates: How to Determine Reliable Protonation Constants from NMR Titration Data
journal, November 2022
- Kalydi, Eszter; Malanga, Milo; Ujj, Dóra
- International Journal of Molecular Sciences, Vol. 23, Issue 22
Cardiac Effects of Opioid Therapy
journal, October 2015
- Chen, Alexander; Ashburn, Michael A.
- Pain Medicine, Vol. 16, Issue suppl 1
The history and development of the fentanyl series
journal, April 1992
- Stanley, Theodore H.
- Journal of Pain and Symptom Management, Vol. 7, Issue 3
Structural modification of fentanyls for their retrospective identification by gas chromatographic analysis using chloroformate chemistry
journal, November 2021
- Valdez, Carlos A.; Leif, Roald N.; Sanner, Robert D.
- Scientific Reports, Vol. 11, Issue 1
Designing small-molecule catalysts for CO2 capture
journal, January 2011
- Wong, Sergio E.; Lau, Edmond Y.; Kulik, Heather J.
- Energy Procedia, Vol. 4
Diazeniumdiolate Ions as Leaving Groups in Anomeric Displacement Reactions: A Protection−Deprotection Strategy for Ionic Diazeniumdiolates
journal, September 2005
- Showalter, Brett M.; Reynolds, Melissa M.; Valdez, Carlos A.
- Journal of the American Chemical Society, Vol. 127, Issue 41
The Amber biomolecular simulation programs
journal, January 2005
- Case, David A.; Cheatham, Thomas E.; Darden, Tom
- Journal of Computational Chemistry, Vol. 26, Issue 16
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes
journal, March 1977
- Ryckaert, Jean-Paul; Ciccotti, Giovanni; Berendsen, Herman J. C.
- Journal of Computational Physics, Vol. 23, Issue 3
Research Progress on Synthesis and Application of Cyclodextrin Polymers
journal, February 2021
- Liu, Yuan; Lin, Ting; Cheng, Cui
- Molecules, Vol. 26, Issue 4
A Series of Forensic Toxicology and Drug Seizure Cases Involving Illicit Fentanyl Alone and in Combination with Heroin, Cocaine or Heroin and Cocaine
journal, October 2014
- Marinetti, Laureen J.; Ehlers, Brooke J.
- Journal of Analytical Toxicology, Vol. 38, Issue 8
Biotin. iv. a Second Synthesis of 2-(δ-Carboxybutyl)-Thiophane-3,4-Dicarboxylic acid
journal, January 1947
- Baker, B. R.; Querry, Merle V.; Bernstein, Seymour
- The Journal of Organic Chemistry, Vol. 12, Issue 1
Comparison of simple potential functions for simulating liquid water
journal, July 1983
- Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.
- The Journal of Chemical Physics, Vol. 79, Issue 2
Supramolecular hosts as in vivo sequestration agents for pharmaceuticals and toxins
journal, January 2020
- Deng, Chun-Lin; Murkli, Steven L.; Isaacs, Lyle D.
- Chemical Society Reviews, Vol. 49, Issue 21
Modified γ-Cyclodextrins and Their Rocuronium Complexes
journal, September 2002
- Cameron, K. S.; Clark, J. K.; Cooper, A.
- Organic Letters, Vol. 4, Issue 20
Countermeasures for Preventing and Treating Opioid Overdose
journal, November 2020
- France, Charles P.; Ahern, Gerard P.; Averick, Saadyah
- Clinical Pharmacology & Therapeutics, Vol. 109, Issue 3
Study to Probe Subsistence of Host-Guest Inclusion Complexes of α and β-Cyclodextrins with Biologically Potent Drugs for Safety Regulatory Dischargement
journal, August 2018
- Rajbanshi, Biplab; Saha, Subhadeep; Das, Koyeli
- Scientific Reports, Vol. 8, Issue 1
Calabadion 1 selectively reverses respiratory and central nervous system effects of fentanyl in a rat model
journal, July 2020
- Thevathasan, Tharusan; Grabitz, Stephanie D.; Santer, Peter
- British Journal of Anaesthesia, Vol. 125, Issue 1
An Efficient, Optimized Synthesis of Fentanyl and Related Analogs
journal, September 2014
- Valdez, Carlos A.; Leif, Roald N.; Mayer, Brian P.
- PLoS ONE, Vol. 9, Issue 9
Unexpected “gas” casualties in Moscow: A medical toxicology perspective
journal, May 2003
- Wax, Paul M.; Becker, Charles E.; Curry, Steven C.
- Annals of Emergency Medicine, Vol. 41, Issue 5
Exploring protein native states and large-scale conformational changes with a modified generalized born model
journal, March 2004
- Onufriev, Alexey; Bashford, Donald; Case, David A.
- Proteins: Structure, Function, and Bioinformatics, Vol. 55, Issue 2
Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models
journal, December 2000
- Kollman, Peter A.; Massova, Irina; Reyes, Carolina
- Accounts of Chemical Research, Vol. 33, Issue 12
A Combined Approach of NMR and Mass Spectrometry Techniques Applied to the α-Cyclodextrin/Moringin Complex for a Novel Bioactive Formulation †
journal, July 2018
- Mathiron, David; Iori, Renato; Pilard, Serge
- Molecules, Vol. 23, Issue 7
pKa of Fentanyl Varies With Temperature: Implications for Acid-Base Management During Extremes of Body Temperature
journal, December 2005
- Thurlkill, Richard L.; Cross, David A.; Scholtz, J. Martin
- Journal of Cardiothoracic and Vascular Anesthesia, Vol. 19, Issue 6
Morphine in acute heart failure: good in relieving symptoms, bad in improving outcomes
journal, September 2017
- Miró, Òscar; Gil, Víctor; Peacock, W. Frank
- Journal of Thoracic Disease, Vol. 9, Issue 9
Determination of Association Constants (Ka) from Solution NMR Data
journal, August 2000
- Fielding, Lee
- Tetrahedron, Vol. 56, Issue 34
Development and testing of a general amber force field
journal, January 2004
- Wang, Junmei; Wolf, Romain M.; Caldwell, James W.
- Journal of Computational Chemistry, Vol. 25, Issue 9
Sulfamethoxazole:hydroxypropyl-β-cyclodextrin complex: preparation and characterization
journal, April 2012
- Garnero, Claudia; Aiassa, Virginia; Longhi, Marcela
- Journal of Pharmaceutical and Biomedical Analysis, Vol. 63
The rising crisis of illicit fentanyl use, overdose, and potential therapeutic strategies
journal, November 2019
- Han, Ying; Yan, Wei; Zheng, Yongbo
- Translational Psychiatry, Vol. 9, Issue 1
Hydrolytic Reactivity Trends among Potential Prodrugs of the O2-Glycosylated Diazeniumdiolate Family. Targeting Nitric Oxide to Macrophages for Antileishmanial Activity
journal, July 2008
- Valdez, Carlos A.; Saavedra, Joseph E.; Showalter, Brett M.
- Journal of Medicinal Chemistry, Vol. 51, Issue 13
Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method
journal, January 2000
- Jakalian, Araz; Bush, Bruce L.; Jack, David B.
- Journal of Computational Chemistry, Vol. 21, Issue 2
UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004
- Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.
- Journal of Computational Chemistry, Vol. 25, Issue 13
Compounds Related to Pethidine--IV. New Genaral Chemical Methods of Increading the Analgesic Activity of Pethidine
journal, February 1960
- J., Paul A.; Eddy, Nathan B.
- Journal of Medicinal and Pharmaceutical Chemistry, Vol. 2, Issue 1
A Novel Strategy to Reverse General Anesthesia by Scavenging with the Acyclic Cucurbit[n]uril-type Molecular Container Calabadion 2
journal, August 2016
- Diaz-Gil, Daniel; Haerter, Friederike; Falcinelli, Shane
- Anesthesiology, Vol. 125, Issue 2
Cyclodextrin–Drug Inclusion Complexes: In Vivo and In Vitro Approaches
journal, February 2019
- Carneiro, Simone; Costa Duarte, Fernanda; Heimfarth, Luana
- International Journal of Molecular Sciences, Vol. 20, Issue 3
Methylation protocol for the retrospective detection of isopropyl-, pinacolyl- and cyclohexylmethylphosphonic acids, indicative markers for the nerve agents sarin, soman and cyclosarin, at low levels in soils using EI-GC–MS
journal, September 2019
- Valdez, Carlos A.; Leif, Roald N.; Hok, Saphon
- Science of The Total Environment, Vol. 683
Water Suppression That Works. Excitation Sculpting Using Arbitrary Wave-Forms and Pulsed-Field Gradients
journal, February 1995
- Hwang, T. L.; Shaka, A. J.
- Journal of Magnetic Resonance, Series A, Vol. 112, Issue 2
Fentanyl Law Enforcement Submissions and Increases in Synthetic Opioid–Involved Overdose Deaths — 27 States, 2013–2014
journal, August 2016
- Gladden, R. Matthew; Martinez, Pedro; Seth, Puja
- MMWR. Morbidity and Mortality Weekly Report, Vol. 65, Issue 33
Solution-State Structure and Affinities of Cyclodextrin:Fentanyl Complexes by Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Simulation
journal, February 2016
- Mayer, Brian P.; Kennedy, Daniel J.; Lau, Edmond Y.
- The Journal of Physical Chemistry B, Vol. 120, Issue 9
Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems
journal, June 1993
- Darden, Tom; York, Darrin; Pedersen, Lee
- The Journal of Chemical Physics, Vol. 98, Issue 12
In Vitro and In Vivo Sequestration of Methamphetamine by a Sulfated Acyclic CB[n]‐Type Receptor
journal, October 2021
- Brockett, Adam T.; Deng, Chunlin; Shuster, Michael
- Chemistry – A European Journal, Vol. 27, Issue 69
Molecular dynamics with coupling to an external bath
journal, October 1984
- Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.
- The Journal of Chemical Physics, Vol. 81, Issue 8
An Operationally Simple Synthesis of Fentanyl Citrate
journal, September 2017
- Walz, Andrew J.; Hsu, Fu-Lian
- Organic Preparations and Procedures International, Vol. 49, Issue 5
Evaluation of a Carbonic Anhydrase Mimic for Industrial Carbon Capture
journal, August 2013
- Floyd, William C.; Baker, Sarah E.; Valdez, Carlos A.
- Environmental Science & Technology, Vol. 47, Issue 17
Complexation Thermodynamics of Cyclodextrins
journal, July 1998
- Rekharsky, Mikhail V.; Inoue, Yoshihisa
- Chemical Reviews, Vol. 98, Issue 5
Sugar-Modified Conjugated Diene Analogues of Adenosine and Uridine: Synthesis, Interaction with S-Adenosyl-l -homocysteine Hydrolase, and Antiviral and Cytostatic Effects
journal, April 2002
- Wnuk, Stanislaw F.; Ro, Bong-Oh; Valdez, Carlos A.
- Journal of Medicinal Chemistry, Vol. 45, Issue 12
Molecular dynamics of fentanyl bound to μ-opioid receptor
journal, May 2019
- Lipiński, Piotr F. J.; Jarończyk, Małgorzata; Dobrowolski, Jan Cz.
- Journal of Molecular Modeling, Vol. 25, Issue 5
Doubly Homologated Dihalovinyl and Acetylene Analogues of Adenosine: Synthesis, Interaction with S-Adenosyl-l -homocysteine Hydrolase, and Antiviral and Cytostatic Effects
journal, March 2000
- Wnuk, Stanislaw F.; Valdez, Carlos A.; Khan, Jahanzeb
- Journal of Medicinal Chemistry, Vol. 43, Issue 6
Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis
journal, February 2019
- Lipiński, Piotr; Kosson, Piotr; Matalińska, Joanna
- Molecules, Vol. 24, Issue 4
Analysis of Clothing and Urine from Moscow Theatre Siege Casualties Reveals Carfentanil and Remifentanil Use
journal, September 2012
- Riches, James R.; Read, Robert W.; Black, Robin M.
- Journal of Analytical Toxicology, Vol. 36, Issue 9
Molecular dynamics studies of native and substituted cyclodextrins in different media: 1. Charge derivation and force field performances
journal, January 2011
- Cézard, Christine; Trivelli, Xavier; Aubry, Frédéric
- Physical Chemistry Chemical Physics, Vol. 13, Issue 33
Analysis of chemical warfare agents by gas chromatography-mass spectrometry: methods for their direct detection and derivatization approaches for the analysis of their degradation products
journal, July 2017
- Valdez, Carlos A.; Leif, Roald N.; Hok, Saphon
- Reviews in Analytical Chemistry, Vol. 37, Issue 1
Cyclodextrins: Emerging Medicines of the New Millennium
journal, November 2019
- Braga, Susana Santos
- Biomolecules, Vol. 9, Issue 12
Sugammadex: A revolutionary drug in neuromuscular pharmacology
journal, January 2013
- Singh, DewanRoshan; Sivashanmugam, T.; Kumar, Hemanth
- Anesthesia: Essays and Researches, Vol. 7, Issue 3
Calculation of Cyclodextrin Binding Affinities: Energy, Entropy, and Implications for Drug Design
journal, November 2004
- Chen, Wei; Chang, Chia-En; Gilson, Michael K.
- Biophysical Journal, Vol. 87, Issue 5
Fentanyl
journal, May 2005
- Stanley, Theodore H.
- Journal of Pain and Symptom Management, Vol. 29, Issue 5
Determining association constants from titration experiments in supramolecular chemistry
journal, January 2011
- Thordarson, Pall
- Chem. Soc. Rev., Vol. 40, Issue 3
Study to explore the mechanism to form inclusion complexes of β-cyclodextrin with vitamin molecules
journal, October 2016
- Saha, Subhadeep; Roy, Aditi; Roy, Kanak
- Scientific Reports, Vol. 6, Issue 1
Synthesis and Monolayer Characterization of Phosphorylated Amino Acid Analogs
journal, October 2002
- Ekeroth, Johan; Borgh, Annika; Konradsson, Peter
- Journal of Colloid and Interface Science, Vol. 254, Issue 2
Review: A History of Cyclodextrins
journal, September 2014
- Crini, Grégorio
- Chemical Reviews, Vol. 114, Issue 21
Effective methylation of phosphonic acids related to chemical warfare agents mediated by trimethyloxonium tetrafluoroborate for their qualitative detection and identification by gas chromatography-mass spectrometry
journal, August 2016
- Valdez, Carlos A.; Leif, Roald N.; Alcaraz, Armando
- Analytica Chimica Acta, Vol. 933
Toward a Small Molecule, Biomimetic Carbonic Anhydrase Model: Theoretical and Experimental Investigations of a Panel of Zinc(II) Aza-Macrocyclic Catalysts
journal, June 2012
- Koziol, Lucas; Valdez, Carlos A.; Baker, Sarah E.
- Inorganic Chemistry, Vol. 51, Issue 12