A computational study of intramolecular hydrogen bonds breaking/formation: impact on the structural flexibility of the ranitidine molecule


Ranitidine is a histamine H2-receptor antagonist that reduces gastric acid secretion. We studied the flexibility of the ranitidine molecule with the special focus on the network of diverse intramolecular hydrogen bonds: N-H ⋯O, N-H ⋯N, C-H ⋯O, C-H ⋯N and N-H ⋯S. We performed static density functional theory calculations of global and local minima and analyzed their stability at finite temperature in the Car–Parrinello molecular dynamics simulations. We observed intramolecular H-bonds breaking/formation crucial for the structural rearrangements leading to the folding process. The lifetimes of the closed structures of ranitidine were also estimated. The existence of hydrogen bonds and their strength were confirmed on the basis of topological parameters in the bond critical points utilizing Quantum Theory of Atoms in Molecules.

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  1. 1.

    Ahmadi A, Ebrahimzadeh MA, Ahmad-Ashrafi S, Karami M, Mahdavi MR, Saravi SSS (2001) Hepatoprotective, antinociceptive and antioxidant activities of cimetidine, ranitidine and famotidine as histamine H2 receptor antagonists. Fundam Clin Pharmacol 25:72

    Article  Google Scholar 

  2. 2.

    Amin AS, Ahmed IS, Dessouki HA, Gouda EA (2003) Utility of oxidation-reduction reaction for the determination of ranitidine hydrochloride in pure form, in dosage forms and in the presence of its oxidative degradates. Spectrochim Acta 59:695

    Article  CAS  Google Scholar 

  3. 3.

    Bader RFW (1990) Atoms in Molecules, A Quantum Theory. Oxford University Press, Oxford

    Google Scholar 

  4. 4.

    Becke AD (1988) Density-functional exchange-energy approximation with correct asymptotic-behavior. Phys Rev A 38:3098

    Article  CAS  Google Scholar 

  5. 5.

    Car R, Parrinello M (1985) Unified approach for molecular-dynamics and density-functional theory. Phys Rev Lett 55:2471

    Article  CAS  Google Scholar 

  6. 6.

    Ching TL, Haenen GR, Bast A (1993) Cimetidine and other H2 receptor antagonists as powerful hydroxyl radical scavengers. Chem Biol Interact 86:119

    Article  CAS  Google Scholar 

  7. 7.

    Fan JM, Liu L, Guo QX (2002) Substituent effects on the blue-shifted hydrogen bonds. Chem Phys Lett 365:464

    Article  CAS  Google Scholar 

  8. 8.

    Ferretti V, Pretto L, Tabrizi MA, Gilli P (2006) Role of strong intramolecular N-H-N hydrogen bonds in determining the conformation of adenosine-receptor antagonists. ActaCryst B62:634

    CAS  Google Scholar 

  9. 9.

    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery J A Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas JB, Foresman JV, Cioslowski Ortiz J, Fox DJ (2009) Gaussian 09, Revision D.01. Gaussian, Inc., Wallingford CT.

  10. 10.

    Gao Y, Tian Y, Sun X, Yin XB, Xiang Q, Ma G, Wang E (2006) Determination of ranitidine in urine by capillary electrophoresis-electrochemiluminescent detection. J Chromatogr B 832:236

    Article  CAS  Google Scholar 

  11. 11.

    Grabowski SJ (2011) Red- and blue-shifted hydrogen bonds: the bent rule from Quantum Theory of Atoms in Molecules perspective. J Phys Chem A 115:12789

    Article  CAS  Google Scholar 

  12. 12.

    Grant SM, Langtry HD, Brogden RN (1989) Ranitidine Drugs 37(6):801

    Article  CAS  Google Scholar 

  13. 13.

    Grimme S (2004) Accurate description of van der Waals complexes by density functional theory including empirical corrections. J Comput Chem 25(12):1463

    Article  CAS  Google Scholar 

  14. 14.

    Gu Y, Kar T, Scheiner S (1999) Fundamental properties of the CH ⋯O interaction: Is it a true hydrogen bond. J Am Chem Soc 121:9411

    Article  CAS  Google Scholar 

  15. 15.

    Hermansson K (2002) Blue-shifting hydrogen bonds. J Phys Chem A 106:4695

    Article  CAS  Google Scholar 

  16. 16.

    Hoover WG (1985) Canonical dynamics — equilibrium phase-space distributions. Phys Rev A 31:1695

    Article  Google Scholar 

  17. 17.


  18. 18.

    Humphrey W, Dalke A, Schulten K (1996) VMD — Visual Molecular Dynamics. J Molec Graphics 14:33

    Article  CAS  Google Scholar 

  19. 19.

    Isidori M, Parrella A, Pistillo P, Temussi F (2009) Effects of ranitidine and its photoderivatives in the aquatic environment. Environ Int 35:821

    Article  CAS  Google Scholar 

  20. 20.

    Jeffrey GA, Saenger W (1991) Hydrogen bonding in biological structures. Springer

  21. 21.

    Karpfen A, Kryachko ES (2003) Blue-shifted hydrogen-bonded complexes cf3h-(hf)1¡n¡3. J Phys Chem A 107:9724

    Article  CAS  Google Scholar 

  22. 22.

    Keith TA (2010) AIMAll (version 10.05.04, professional)

  23. 23.

    Khalil MM, Frag EYZ, Mohamed GG, Abed el Aziz GM (2013) Spectrophotometric studies using ion-pair formations of ranitidine hydrochloride in pure and in pharmaceutical forms with some dyestuff reagents. JAPS 3(04):092

    CAS  Google Scholar 

  24. 24.

    Koch U, Popelier PLA (1995) Characterization of C-H-O hydrogen bonds on the basis of the charge density. J Phys Chem 99:9747

    Article  CAS  Google Scholar 

  25. 25.

    Kokoletsi MX, Kafkala S, Tsiaganis M (2005) A novel gradient HPLC method for simultaneous determination of ranitidine, methylparaben and propylparaben in oral liquid pharmaceutical formulation. J Pharm Biomed Anal 38:763

    Article  CAS  Google Scholar 

  26. 26.

    Kryachko ES, Zeegers-Huyskens Th (2001) Theoretical study of the ch ⋯o interaction in fluoromethanesh2o and chloromethanesh2o complex. J Phys Chem A 105:7118

    Article  CAS  Google Scholar 

  27. 27.

    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

    Article  CAS  Google Scholar 

  28. 28.

    Martins JL, Perez MA, Silva CH, Taft CA, Arissawa M, Longo E, Mello PC, Stamato F, Tostes JG (2002) Theoretical ab initio study of ranitidine. Int J Quantum Chem 90:575

    Article  CAS  Google Scholar 

  29. 29.

    Martyna GJ, Tuckerman ME (1999) A reciprocal space based method for treating long range interactions in ab initio and force-field-based calculations in clusters. J Chem Phys 119:2810

    Article  Google Scholar 

  30. 30.

    Nose S (1984) A unified formulation of the constant temperature molecular-dynamics methods. J Chem Phys 81:511

    Article  CAS  Google Scholar 

  31. 31.

    Pfaffen V, Ortiz PI (2010) Alternative method with amperometric detection for ranitidine determination. Ind Eng Chem Res 49:4026

    Article  CAS  Google Scholar 

  32. 32.

    Pimentel GC, McClellan AL (1971) Hydrogen bonding. Annu Rev Phys Chem 21:347

    Article  Google Scholar 

  33. 33.

    Rodziewicz P, Meyer B (2014) Interplay between molecule—molecule and molecule—substrate interactions: first principles study of fluoroform aggregates on a hexagonal ice (0001) surface. Phys Chem Chem Phys 16:940

    Article  CAS  Google Scholar 

  34. 34.

    Rodziewicz P, Rutkowski KS, Meyer B (2011) First-principles study of fluoroform adsorption on a hexagonal ice (0001) surface; weak hydrogen bonds–strong structural effects. Phys Chem Chem Phys 13:14101

    Article  CAS  Google Scholar 

  35. 35.

    Rodziewicz P, Rutkowski KS, Melikova SM, Koll A (2005) Ab initio studies of electron acceptor–donor interactions with blue- and red-shifted hydrogen bonds. ChemPhysChem 6: 1282

    Article  CAS  Google Scholar 

  36. 36.

    Van der Veken BJ, Herrebout WA, Szostak R, Shchepkin DN, Havlas Z, Hobza P (2001) The nature of improper, blue-shifting hydrogen bonding verified experimentally. J Am Chem Soc 123:12290

    Article  Google Scholar 

  37. 37.

    Wojtulewski S, Grabowski SJ (2005) Blue-shifting C—H⋯Y intramolecular hydrogen bonds—DFT and AIM analyses. Chem. Phys. 309:183

    Article  CAS  Google Scholar 

  38. 38.

    Wright R (1996) How Zantac became the best-selling drug in history, vol 16, p 4

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One of the authors of the publication, Mariana Kozlowska, is a beneficiary of the project “Scholarship for PhD students of Podlaskie Voivodeship”. The project is co-financed by European Social Fund, Polish Government and Podlaskie Voivodeship.

All calculations were performed at the Interdisciplinary Centre for Mathematical and Computational Modelling (ICM) at Warsaw University under a grant No. G55-1.

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Correspondence to Mariana Kozlowska.

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Kozlowska, M., Goclon, J. & Rodziewicz, P. A computational study of intramolecular hydrogen bonds breaking/formation: impact on the structural flexibility of the ranitidine molecule. J Mol Model 21, 94 (2015). https://doi.org/10.1007/s00894-015-2591-7

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  • Ranitidine
  • Intramolecular hydrogen bonds
  • AIM analysis
  • Car-Parrinello molecular dynamics
  • Structural flexibility