Affinity of Nicotinoids to a Model Nicotinic Acetylcholine Receptor (nAChR) Binding Pocket in the Human Brain

Santis, Garrett D.; Okura, Yuika; Hirata, Keisuke; Ishiuchi, Shun-Ichi; Fujii, Masaaki; Xantheas, Sotiris S.

doi:10.1021/acs.jpcb.3c07919

Affinity of Nicotinoids to a Model Nicotinic Acetylcholine Receptor (nAChR) Binding Pocket in the Human Brain

Journal Article · Thu May 02 00:00:00 EDT 2024 · Journal of Physical Chemistry. B

DOI:https://doi.org/10.1021/acs.jpcb.3c07919· OSTI ID:2475141

Santis, Garrett D. ^[1]; Okura, Yuika ^[2]; Hirata, Keisuke ^[2]; Ishiuchi, Shun-Ichi ^[2]; ^[3]; ^[4]

University of Washington, Seattle, WA (United States)
Tokyo Intitute of Technology (Japan)
Tokyo Intitute of Technology (Japan); Chuo University, Tokyo (Japan)
University of Washington, Seattle, WA (United States); Tokyo Institute of Technology, Yokohama (Japan); Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

The binding affinity of nicotinoids to the binding residues of the a4ß2 variant of the nicotinic acetylcholine receptor (nAChR) was identified as a strong predictor of the nicotinoid’s addictive character. Using ab-iniito calculations for model binding pockets of increasing size comprising of 3, 6, and 14 amino acids (3AA, 6AA, and 14AA) that are derived from the crystal structure, the differences in binding affinity of 6 nicotinoids, namely nicotine (NIC), nornicotine (NOR), anabasine (ANB), anatabine (ANT), myosmine (MYO), and cotinine (COT) were correlated to their previously reported doses required for increases in intracranial self-stimulation (ICSS) thresholds, a metric for their addictive function. By employing the many body decomposition, the differences in the binding affinities of the various nicotinoids could be attributed mainly to the proton exchange energy between the Pyridine and non-Pyridine rings of the nicotinoids and the interactions between them and a handful of proximal amino acids, namely Trp156, Trpß57, Tyr100, and Tyr204. Interactions between the guest nicotinoid and the amino acids of the binding pocket were found to be mainly classical in nature, except for those between the nicotinoid and Trp156. The larger pockets were found to model binding structures more accurately and predicted the addictive character of all nicotinoids while smaller models, which are more computationally feasible, would only predict the addictive character of nicotinoids that are similar to nicotine. Here, the present study identifies the binding affinity of the guest nicotinoid to the host binding pocket as a strong descriptor of the nicotinoid’s addiction potential and as such it can be employed as a fast screening technique for the potential addiction of nicotine analogs.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division (CSGB)

Grant/Contract Number:: AC02-05CH11231; AC05-76RL01830

OSTI ID:: 2475141

Report Number(s):: PNNL-SA--197284

Journal Information:: Journal of Physical Chemistry. B, Journal Name: Journal of Physical Chemistry. B Journal Issue: 19 Vol. 128; ISSN 1520-6106

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

References (40)

Which density functional is close to CCSD accuracy to describe geometry and interaction energy of small noncovalent dimers? A benchmark study using Gaussian09 Remya, Karunakaran; Suresh, Cherumuttathu H. Journal of Computational Chemistry, Vol. 34, Issue 15 https://doi.org/10.1002/jcc.23263	journal	March 2013
Efficient diffuse function-augmented basis sets for anion calculations. III. The 3-21+G basis set for first-row elements, Li-F Clark, Timothy; Chandrasekhar, Jayaraman; Spitznagel, G�nther W. Journal of Computational Chemistry, Vol. 4, Issue 3 https://doi.org/10.1002/jcc.540040303	journal	October 1983
The influence of polarization functions on molecular orbital hydrogenation energies Hariharan, P. C.; Pople, J. A. Theoretica Chimica Acta, Vol. 28, Issue 3 https://doi.org/10.1007/BF00533485	journal	January 1973
Nicotinic acetylcholine receptors: from structure to brain function Hogg, R. C.; Raggenbass, M.; Bertrand, D. Reviews of Physiology, Biochemistry and Pharmacology https://doi.org/10.1007/s10254-003-0005-1	book	January 2003
Cellular mechanisms of nicotine addiction Dani, John A.; De Biasi, Mariella Pharmacology Biochemistry and Behavior, Vol. 70, Issue 4 https://doi.org/10.1016/S0091-3057(01)00652-9	journal	December 2001
Effects of nicotine and minor tobacco alkaloids on intracranial-self-stimulation in rats Harris, Andrew C.; Tally, Laura; Muelken, Peter Drug and Alcohol Dependence, Vol. 153 https://doi.org/10.1016/j.drugalcdep.2015.06.005	journal	August 2015
Gating Movement of Acetylcholine Receptor Caught by Plunge-Freezing Unwin, Nigel; Fujiyoshi, Yoshinori Journal of Molecular Biology, Vol. 422, Issue 5 https://doi.org/10.1016/j.jmb.2012.07.010	journal	October 2012
Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic Receptor Gharpure, Anant; Teng, Jinfeng; Zhuang, Yuxuan Neuron, Vol. 104, Issue 3 https://doi.org/10.1016/j.neuron.2019.07.030	journal	November 2019
Alpha 7 nicotinic acetylcholine receptor and its effects on Alzheimer's disease Ma, Kai-Ge; Qian, Yi-Hua Neuropeptides, Vol. 73 https://doi.org/10.1016/j.npep.2018.12.003	journal	February 2019
OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules Roos, Katarina; Wu, Chuanjie; Damm, Wolfgang Journal of Chemical Theory and Computation, Vol. 15, Issue 3 https://doi.org/10.1021/acs.jctc.8b01026	journal	January 2019
Quantum Mechanical Continuum Solvation Models Tomasi, Jacopo; Mennucci, Benedetta; Cammi, Roberto Chemical Reviews, Vol. 105, Issue 8 https://doi.org/10.1021/cr9904009	journal	August 2005
The ionic hydrogen bond and ion solvation. 1. NH+.cntdot..cntdot..cntdot.O, NH+.cntdot..cntdot..cntdot.N, and OH+.cntdot..cntdot..cntdot.O bonds. Correlations with proton affinity. Deviations due to structural effects Mautner, Michael Journal of the American Chemical Society, Vol. 106, Issue 5 https://doi.org/10.1021/ja00317a015	journal	March 1984
Self-consistent molecular-orbital methods. 22. Small split-valence basis sets for second-row elements Gordon, Mark S.; Binkley, J. Stephen; Pople, John A. Journal of the American Chemical Society, Vol. 104, Issue 10 https://doi.org/10.1021/ja00374a017	journal	May 1982
Anabasine Linnell, Robert H. Journal of the American Chemical Society, Vol. 76, Issue 5 https://doi.org/10.1021/ja01634a077	journal	March 1954
Site of Protonation of Nicotine and Nornicotine in the Gas Phase: Pyridine or Pyrrolidine Nitrogen? Graton, Jérôme; Berthelot, Michel; Gal, Jean-François Journal of the American Chemical Society, Vol. 124, Issue 35 https://doi.org/10.1021/ja017770a	journal	August 2002
Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids Jorgensen, William L.; Maxwell, David S.; Tirado-Rives, Julian Journal of the American Chemical Society, Vol. 118, Issue 45 https://doi.org/10.1021/ja9621760	journal	January 1996
Structure of Gas Phase Monohydrated Nicotine: Implications for Nicotine’s Native Structure in the Acetylcholine Binding Protein Santis, Garrett D.; Takeda, Naoya; Hirata, Keisuke Journal of the American Chemical Society, Vol. 144, Issue 37 https://doi.org/10.1021/jacs.2c04064	journal	August 2022
Quantitative determination of the ring-chain hydrolysis equilibrium constant for anabaseine and related tobacco alkaloids Zoltewicz, John A.; Bloom, Linda B.; Kem, William R. The Journal of Organic Chemistry, Vol. 54, Issue 18 https://doi.org/10.1021/jo00279a042	journal	September 1989
Isomers and Conformational Barriers of Gas-Phase Nicotine, Nornicotine, and Their Protonated Forms Yoshida, Tomoki; Farone, William A.; Xantheas, Sotiris S. The Journal of Physical Chemistry B, Vol. 118, Issue 28 https://doi.org/10.1021/jp501646p	journal	April 2014
Density Functional Theory of Electronic Structure Kohn, W.; Becke, A. D.; Parr, R. G. The Journal of Physical Chemistry, Vol. 100, Issue 31 https://doi.org/10.1021/jp960669l	journal	January 1996
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors Brejc, KatjuS̆a; van Dijk, Willem J.; Klaassen, Remco V. Nature, Vol. 411, Issue 6835 https://doi.org/10.1038/35077011	journal	May 2001
X-ray structure of the human α4β2 nicotinic receptor Morales-Perez, Claudio L.; Noviello, Colleen M.; Hibbs, Ryan E. Nature, Vol. 538, Issue 7625 https://doi.org/10.1038/nature19785	journal	October 2016
Structural basis of human α7 nicotinic acetylcholine receptor activation Zhao, Yue; Liu, Sanling; Zhou, Yingxin Cell Research, Vol. 31, Issue 6 https://doi.org/10.1038/s41422-021-00509-6	journal	May 2021
Structural principles of distinct assemblies of the human α4β2 nicotinic receptor Walsh, Richard M.; Roh, Soung-Hun; Gharpure, Anant Nature, Vol. 557, Issue 7704 https://doi.org/10.1038/s41586-018-0081-7	journal	May 2018
Spectroscopic investigations into the acid–base properties of nicotine at different temperatures Clayton, Peter M.; Vas, Carl A.; Bui, Tam T. T. Anal. Methods, Vol. 5, Issue 1 https://doi.org/10.1039/C2AY25678A	journal	January 2013
Gas phase protonated nicotine is a mixture of pyridine- and pyrrolidine-protonated conformers: implications for its native structure in the nicotinic acetylcholine receptor Takeda, Naoya; Hirata, Keisuke; Tsuruta, Kazuya Physical Chemistry Chemical Physics, Vol. 24, Issue 10 https://doi.org/10.1039/D1CP05175J	journal	January 2022
A critical comparison of CH⋯π versus π⋯π interactions in the benzene dimer: obtaining benchmarks at the CCSD(T) level and assessing the accuracy of lower scaling methods Herman, Kristina M.; Aprà, Edoardo; Xantheas, Sotiris S. Physical Chemistry Chemical Physics, Vol. 25, Issue 6 https://doi.org/10.1039/D2CP04335A	journal	January 2023
Long-range corrected hybrid density functionals with damped atom–atom dispersion corrections Chai, Jeng-Da; Head-Gordon, Martin Physical Chemistry Chemical Physics, Vol. 10, Issue 44 https://doi.org/10.1039/b810189b	journal	January 2008
Protonating and determining myosmine intactly by association with citrate anion Chen, Bo; Xu, Qingping The Analyst, Vol. 136, Issue 22 https://doi.org/10.1039/c1an15611j	journal	January 2011
Water Molecule Interactions Hankins, D.; Moskowitz, J. W.; Stillinger, F. H. The Journal of Chemical Physics, Vol. 53, Issue 12 https://doi.org/10.1063/1.1673986	journal	December 1970
Self‐consistent molecular orbital methods. XXIII. A polarization‐type basis set for second‐row elements Francl, Michelle M.; Pietro, William J.; Hehre, Warren J. The Journal of Chemical Physics, Vol. 77, Issue 7, p. 3654-3665 https://doi.org/10.1063/1.444267	journal	October 1982
Natural population analysis Reed, Alan E.; Weinstock, Robert B.; Weinhold, Frank The Journal of Chemical Physics, Vol. 83, Issue 2 https://doi.org/10.1063/1.449486	journal	July 1985
Ab initio studies of cyclic water clusters (H ₂ O) _n , n =1–6. II. Analysis of many‐body interactions Xantheas, Sotiris S. The Journal of Chemical Physics, Vol. 100, Issue 10 https://doi.org/10.1063/1.466846	journal	May 1994
Alpha7 Nicotinic Receptors as Therapeutic Targets in Schizophrenia Tregellas, Jason R.; Wylie, Korey P. Nicotine & Tobacco Research, Vol. 21, Issue 3 https://doi.org/10.1093/ntr/nty034	journal	August 2018
Molecular dynamics studies of AChBP with nicotine and carbamylcholine: the role of water in the binding pocket Amiri, S.; Sansom, M. S. P.; Biggin, P. C. Protein Engineering Design and Selection, Vol. 20, Issue 7 https://doi.org/10.1093/protein/gzm029	journal	March 2007
The pharmacological activity of nicotine and nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery: Nornicotine activation of nAChR Papke, Roger L.; Dwoskin, Linda P.; Crooks, Peter A. Journal of Neurochemistry, Vol. 101, Issue 1 https://doi.org/10.1111/j.1471-4159.2006.04355.x	journal	February 2007
Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs Negus, S. Stevens; Miller, Laurence L. Pharmacological Reviews, Vol. 66, Issue 3 https://doi.org/10.1124/pr.112.007419	journal	June 2014
α7-Nicotinic Acetylcholine Receptor Agonists for Cognitive Enhancement in Schizophrenia Freedman, Robert Annual Review of Medicine, Vol. 65, Issue 1 https://doi.org/10.1146/annurev-med-092112-142937	journal	January 2014
Pharmacology of Nicotine: Addiction, Smoking-Induced Disease, and Therapeutics Benowitz, Neal L. Annual Review of Pharmacology and Toxicology, Vol. 49, Issue 1 https://doi.org/10.1146/annurev.pharmtox.48.113006.094742	journal	February 2009
FACILITATION OF HUMAN TOBACCO SELF-ADMINISTRATION BY ETHANOL: A BEHAVIORAL ANALYSIS ¹ Griffiths, Roland R.; Bigelow, George E.; Liebson, Ira Journal of the Experimental Analysis of Behavior, Vol. 25, Issue 3 https://doi.org/10.1901/jeab.1976.25-279	journal	May 1976

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60 APPLIED LIFE SCIENCES
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Affinity of Nicotinoids to a Model Nicotinic Acetylcholine Receptor (nAChR) Binding Pocket in the Human Brain

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