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Effects of intramolecular hydrogen bonding on nuclear magnetic resonance, electron paramagnetic resonance and molecular docking studies: Mexiletine molecule

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Abstract

Context

In this study, the molecular structure of the mexiletine molecule was investigated. Since the Mexiletine molecule is a drug active ingredient, its molecular structure and spectroscopic properties are important. The effects of intramolecular hydrogen bonding on Nuclear Magnetic Resonance Parameters (NMR), Electron Paramagnetic Resonance (EPR) parameters and molecular docking studies were examined in the mexiletine molecule. The effects of intramolecular hydrogen bonding on EPR parameters and molecular docking studies are the most important steps for this study.

Method

Conformational space scanning required for molecular structure calculations was carried out with the Molecular Mechanic Force Field method. DFT method with 6–311 +  + G(d,p) basis set level was used to obtain the most stable structure among the conformations. NMR parameters (1H and 13C chemical shift values) were also performed using the same basis set as the DFT method. The radicals created to calculate the Electron Paramagnetic Resonance parameters were modeled using the DFT/B3LYP/6–311 +  + G(d,p) method basis set level. Molecular Docking studies were carried out with the Autodock vina program.

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The author undertakes to share any data used in this study with the requesting person or institution upon request.

References

  1. Fenster PE, Comess KA (1986) Pharmacology and clinical use of mexiletine. Pharmacotherapy 6:1–9. https://doi.org/10.1002/j.1875-9114.1986.tb03442.x

    Article  CAS  PubMed  Google Scholar 

  2. Hill RJ, Duff HJ, Sheldon RS (1988) Determinants of stereospecific binding of type I antiarrhythmic drugs to cardiac sodium channels. Mol Pharmacol 34(5):659–663

    CAS  PubMed  Google Scholar 

  3. De Luca A, Natuzzi F, Lentini G, Franchini C, Tortorella V, Conte Camerino D (1995) Stereoselective effects of mexiletine enantiomers on sodium currents and excitability characteristics of adult skeletal muscle fibers. Naunyn Schmiedebergs Arch Pharmakol 352(6):653–661. https://doi.org/10.1007/BF00171325

    Article  Google Scholar 

  4. Turgeon J, Uprichard ACG, Be’langer PM, Harron DWG, Grech-Be’langer O (1991) Resolution and electrophysiological effects of mexiletine enantiomers. J Pharm Pharmacol 43(9):630–635.https://doi.org/10.1111/j.2042-7158.1991.tb03552.x

  5. De Luca A, Natuzzi F, Falcone G, Duranti A, Lentini G, Franchini C, Tortorella V, Conte Camerino D (1997) Inhibition of frog skeletal muscle sodium channels by newly synthesized chiral derivatives of mexiletine and tocainide. Naunyn-Schmiedebergs Arch Pharmacol 356(6):777–787. https://doi.org/10.1007/PL00005118

    Article  PubMed  Google Scholar 

  6. Cavalluzzi MM, Catalano A, Bruno C, Lovece A, Carocci A, Corbo F, Franchini C, Lentini G, Tortorella V (2007) Synthesis of (R)-, (S)-, and (RS)-hydroxymethylmexiletine, one of the major metabolites of mexiletine. Tetrahedron Asymmetry 18(20):2409–2417. https://doi.org/10.1016/j.tetasy.2007.10.002

    Article  CAS  Google Scholar 

  7. De Luca A, Natuzzi F, Desaphy JF, Loni G, Lentini G, Franchini C, Tortorella V, Conte CD (2000) Molecular determinants of mexiletine structure for potent and use-dependent block of skeletal muscle sodium channels. Mol Pharmacol 57:268–277

    PubMed  Google Scholar 

  8. Wijmenga SS, Van Buuren BNM (1998) The use of NMR methods for conformational studies of nucleic acids. Prog Nucl Magn Reson Spectrosc 32(4):287–387. https://doi.org/10.1016/S0079-6565(97)00023-X

    Article  CAS  Google Scholar 

  9. Shao Y, Molnar L, Jung Y, Kussmann J, Ochsenfeld C, Brown S, Gilbert A, Slipchenko L, Levchenko S, O’Neill D (2006) Spartan’08, Wavefunction, Inc., Irvine, CA. Phys Chem Chem Phys 8:3172–3191. https://doi.org/10.1039/B517914A

    Article  CAS  PubMed  Google Scholar 

  10. Chesnut DB (1994) Ab initio calculations of NMR chemical shielding. Annu Rep NMR Spectrosc 29:71–122. https://doi.org/10.1016/S0066-4103(08)60131-3

    Article  CAS  Google Scholar 

  11. de Dios AC (1996) Ab initio calculations of the NMR chemical shift. Progr Magn Reson Spectrosc 29:229–278. https://doi.org/10.1016/S0079-6565(96)01029-1

    Article  Google Scholar 

  12. Barszczewicz A, Jaszúnski M, Jackowski K (1993) K. Ab initio calculations of the oxygen atom NMR shielding in the carbonyl group. Chem Phys Lett 203(4):404–408. https://doi.org/10.1016/0009-2614(93)85589-G

  13. Tahtinen P, Bagno A, Klia KD, Pihlaja K (2003) Modeling NMR parameters by DFT methods as an aid to the conformational analysis of cis-fused 7a(8a)-methyl Octa(hexa)hydrocyclopenta[d][1,3]oxazines and [3,1]benzoxazines. J Am Chem Soc 125(15):4609–4618. https://doi.org/10.1021/ja021237t

    Article  CAS  PubMed  Google Scholar 

  14. Kupka T, Koøaski M, Pasterna G, Ruud K (1999) Towards more reliable prediction of formaldehyde multinuclear NMR parameters and harmonic vibrations in the gas phase and solution. J Mol Struct (THEOCHEM) 467(1):63–78. https://doi.org/10.1016/S0166-1280(98)00480-1

    Article  Google Scholar 

  15. Ece E, Tasdemir HU, Biyik R, Ozmen A, Sayin U (2022) Paramagnetic characterization and dosimetric properties of airfix drug and its ingredients (montelukast sodium, sorbitol): An EPR and DFT study. Radiat Phys Chem 195:110082. https://doi.org/10.1016/j.radphyschem.2022.110082

    Article  CAS  Google Scholar 

  16. Ece E, Ozmen A, Biyik R, Sayin U (2023) Gamma irradiation effect on some asthma drugs: EPR detection of radiosterilization. Radiat Prot Dosimetry 199(14):1600–1604. https://doi.org/10.1093/rpd/ncad165

    Article  CAS  Google Scholar 

  17. Tasdemir HU, Türkkan E, Sayin U, Ozmen A (2016) EPR study of gamma-irradiated 2-Bromo-4′-methoxyacetophenone single crystals. Radiat Eff Defects Solids 171(3–4):214–222. https://doi.org/10.1080/10420150.2016.1170017

    Article  ADS  CAS  Google Scholar 

  18. Tasdemir HU, Sayin U, Türkkan E, Ozmen A (2016) EPR investigation of gamma irradiated single crystal guaifenesin: A combined experimental and computational study. Radiat Phys Chem 121:61–68. https://doi.org/10.1016/j.radphyschem.2015.12.016

    Article  ADS  CAS  Google Scholar 

  19. Fan J, Fu A, Zhang L (2019) Progress in molecular docking. Quant Biol 7(2):83–89. https://doi.org/10.1007/s40484-019-0172-y

    Article  CAS  Google Scholar 

  20. Sansen S, Yano JK, Reynald RL, Schoch GA, Griffin KJ, Stout CD, Johnson EF (2007) Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2*. J Biol Chem 282(19):14348–14355. https://doi.org/10.1074/jbc.M611692200

    Article  CAS  PubMed  Google Scholar 

  21. Becke AD (1993) Density functional thermochemistry. III. The role of exact exchange. J Chem Phys 98(7):5648–5652. https://doi.org/10.1063/1.464913

  22. Lee C, Yang W, Parr RG (1988) Development of the Colle- Salvetti correlation- energy formula into a functional of the electron density. Phys Rev B 37:785–789. https://doi.org/10.1103/PhysRevB.37.785

    Article  ADS  CAS  Google Scholar 

  23. Frisch MJ, Trucks GW, Schlegel HB et al (2003) Gaussian 03, Revision E.01. Gaussian, Inc., Pittsburgh, PA

  24. Trott O, Olson AJ (2010) AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461. https://doi.org/10.1002/jcc

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. https://www.rcsb.org/structure/2HI4. Accessed 11.05.2023

  26. Espinosa E, Molins E, Lecomte C (1998) Hydrogen bond strengths revealed by topological analyses of experimentally observed electron densities. Chem Phys Lett 285:170–173. https://doi.org/10.1016/S0009-2614(98)00036-0

    Article  ADS  CAS  Google Scholar 

  27. Okulik N, Jubert AH (2005) Theoretical analysis of the reactive sites of non–steroidal anti–inflammatory drugs. Internet Electron J Mol Des 4:17–30

    CAS  Google Scholar 

  28. Malek K, Vala M, Kozlowski H, Proniewicz LM (2004) Experimental and theoretical NMR study of selected oxocarboxylic acid oximes. Magn Reson Chem 42(1):23–29. https://doi.org/10.1002/mrc.1289

    Article  CAS  PubMed  Google Scholar 

  29. Hori S, Yamauchi K, Kuroki S, Ando I (2002) Proton NMR chemical shift behavior of hydrogen-bonded amide proton of glycine-containing peptides and polypeptides as studied by ab initio MO calculation. Int J Mol Sci 3(8):907–913. https://doi.org/10.3390/i3080907

    Article  CAS  Google Scholar 

  30. Tasdemir HU, Sevgi F, Türkkan E (2019) Determination of 1H and 13C nuclear magnetic resonance chemical shift values of glyoxime molecule with experimental and theoretical methods. Adıyaman Univ J Sci 9(1):99–112

    Google Scholar 

  31. Giacoppo JOS, França TCC, Kuca K, da Cunha EFF, Abagyan R, Mancini DT, Ramalho TC (2014) Molecular modeling and in vitro reactivation study between the oxime BI-6 and acetylcholinesterase inhibited by different nerve agents. J Biomol Struct Dyn 33(9):2048–2058. https://doi.org/10.1080/07391102.2014.989408

    Article  CAS  PubMed  Google Scholar 

  32. Kuca K, Musilek K, Jun D, Zdarova-Karasova J, Nepovimova E, Soukup O, Hrabinova M, Mikler J, Franca TCC, da Cunha EFF, De Castro AA, Valis M, Ramalho TC (2018) A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase. BMC Pharmacol Toxicol 19(8). https://doi.org/10.1186/s40360-018-0196-3.

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Authors and Affiliations

  1. Ahmet Kelesoglu Education Faculty, Physics Department, Necmettin Erbakan University, Konya, Turkey

    Halil Ugur Tasdemir

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Halil Ugur Tasdemir carried out all the calculations. Halil Ugur Tasdemir wrote the main manuscript text.Halil Ugur Tasdemir reviewed the manuscript.

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Correspondence to Halil Ugur Tasdemir.

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Tasdemir, H.U. Effects of intramolecular hydrogen bonding on nuclear magnetic resonance, electron paramagnetic resonance and molecular docking studies: Mexiletine molecule. J Mol Model 30, 41 (2024). https://doi.org/10.1007/s00894-024-05838-y

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  • DOI: https://doi.org/10.1007/s00894-024-05838-y

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