Journal of Molecular Modeling

, Volume 18, Issue 1, pp 103–114 | Cite as

Computer-assisted design for paracetamol masking bitter taste prodrugs

Original Paper


It is believed that the bitter taste of paracetamol, a pain killer drug, is due to its hydroxyl group. Hence, it is expected that blocking the hydroxy group with a suitable linker could inhibit the interaction of paracetamol with its bitter taste receptor/s and hence masking its bitterness. Using DFT theoretical calculations we calculated proton transfers in ten different Kirby’s enzyme models, 1–10. The calculation results revealed that the reaction rate is linearly correlated with the distance between the two reactive centers (rGM) and the angle of the hydrogen bonding (α) formed along the reaction pathway. Based on these results three novel tasteless paracetamol prodrugs were designed and the thermodynamic and kinetic parameters for their proton transfers were calculated. Based on the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for processes 1–10 we have calculated the t1/2 values for the conversion of the three prodrugs to the parental drug, paracetamol. The calculated t1/2 values for ProD 1–3 were found to be 21.3 hours, 4.7 hours and 8 minutes, respectively. Thus, the rate by which the paracetamol prodrug undergoes cleavage to release paracetamol can be determined according to the nature of the linker of the prodrug (Kirby’s enzyme model 1–10). Further, blocking the phenolic hydroxyl group by a linker moiety is believed to hinder the paracetamol bitterness.


Conversion of bitterless paracetamol prodrug to bitter paracetamol via an electron transfer process


DFT calculations Kirby’s enzyme models Masking bitter taste Paracetamol prodrugs Proton transfer reaction 



The Karaman Co. is thanked for support of our computational facilities. Special thanks are also given to Angi Karaman, Donia Karaman, Rowan Karaman and Nardene Karaman for technical assistance.

Supplementary material

894_2011_1040_MOESM1_ESM.doc (168 kb)
ESM 1 (DOC 168 kb)


  1. 1.
    Remington RWJ (2002) The science and practice of pharmacy, 20th edn. Mack publishing company, Easton, pp 1018–1020Google Scholar
  2. 2.
    Brahmankar DM, Jaiswal SB (1995) Biopharmaceutics & pharmaceutics, 1st edn. Vallabh Prakashan, Delhi, pp 162–165Google Scholar
  3. 3.
    Kuchekar BS, Badhan AC, Mahajan HS (2003) Mouth dissolving tablets: a novel drug delivery system. Pharma Times 35:7–9Google Scholar
  4. 4.
    Ley JP (2008) Masking bitter taste by molecules. Chem Precept Chem Precept 1:58–77CrossRefGoogle Scholar
  5. 5.
    Chandreshekar J, Mueller K, Hoon MA, Adler E, Feng L, Guo W, Zuker CS, Ryba NJP (2000) T2Rs function as bitter taste receptor. Cell (Cambridge, Mass) 100:703–711CrossRefGoogle Scholar
  6. 6.
    Scotti L, Scotti MT, Ishiki HM, Ferreira MGP, Emerenciano VP, Menezes CMS, Ferreira EI (2007) Quantitative elucidation of the structure-bittereness relationship of cynaropicrin and grosheimin derivatives. Food Chem 105:77–83CrossRefGoogle Scholar
  7. 7.
  8. 8.
  9. 9.
  10. 10.
    Karaman R (2008) Analysis of Menger's spatiotemporal hypothesis. Tetrahedron Lett 49:5998–6002CrossRefGoogle Scholar
  11. 11.
    Karaman R (2009) A new mathematical equation relating activation energy to bond angle and distance: a key for understanding the role of acceleration in the lactonization of the trimethyl lock system. Bioorg Chem 37:11–25CrossRefGoogle Scholar
  12. 12.
    Karaman R (2009) Reevaluation of Bruice's proximity orientation. Tetrahedron Lett 50:452–456CrossRefGoogle Scholar
  13. 13.
    Karaman R (2009) Accelerations in the lactonization of trimethyl lock systems is due to proximity orientation and not to strain effects. Res Lett Org Chem. doi: 10.1155/2009/240253, 5 pagesGoogle Scholar
  14. 14.
    Karaman R (2009) The effective molarity (EM) puzzle in proton transfer reactions. Bioorg Chem 37:106–110CrossRefGoogle Scholar
  15. 15.
    Karaman R (2009) Cleavage of Menger’s aliphatic amide: a model for peptidase enzyme solely explained by proximity orientation in intramolecular proton transfer. J Mol Struct THEOCHEM 910:27–33CrossRefGoogle Scholar
  16. 16.
    Karaman R (2009) The gem-disubstituent effect-computational study that exposes the relevance of existing theoretical models. Tetrahedron Lett 50:6083–6087CrossRefGoogle Scholar
  17. 17.
    Karaman R (2010) Effects of substitution on the effective molarity (EM) for five membered ring-closure reactions- a computational approach. J Mol Struct THEOCHEM 939:69–74CrossRefGoogle Scholar
  18. 18.
    Karaman R (2009) Analyzing Kirby’s amine olefin – a model for amino-acid ammonia lyases. Tetrahedron Lett 50:7304–7309CrossRefGoogle Scholar
  19. 19.
    Karaman R (2010) The effective molarity (EM) puzzle in intramolecular ring-closing reactions. J Mol Struct THEOCHEM 940:70–75CrossRefGoogle Scholar
  20. 20.
    Karaman R (2010) The efficiency of proton transfer in Kirby's enzyme model, a computational approach. Tetrahedron Lett 51:2130–2135CrossRefGoogle Scholar
  21. 21.
    Karaman R (2010) Proximity vs. strain in ring-closing reactions of bifunctional chain molecules- a computational approach. J Mol Phys 108:1723–1730CrossRefGoogle Scholar
  22. 22.
    Karaman R (2010) The effective molarity (EM) – a computational approach. Bioorg Chem 38:165–172CrossRefGoogle Scholar
  23. 23.
    Karaman R (2010) A general equation correlating intramolecular rates with “attack” parameters distance and angle. Tetrahedron Lett 51:5185–5190CrossRefGoogle Scholar
  24. 24.
    Karaman R, Alfalah S (2010) Multi transition states in SN2 intramolecular reactions. Int Rev Biophys Chem 1:14–23Google Scholar
  25. 25.
    Karaman R, Pascal R (2010) A computational analysis of intramolecularity in proton transfer reactions. Org Bimol Chem 8:5174–5178CrossRefGoogle Scholar
  26. 26.
    Karaman R, Hallak H (2010) Anti-malarial pro-drugs- a computational aided design. Chem Biol Drug Des 76:350–360CrossRefGoogle Scholar
  27. 27.
    Karaman R (2010) Prodrugs of Aza nucleosides based on proton transfer reactions. J Comput Mol Des 24:961–970CrossRefGoogle Scholar
  28. 28.
    Milstein S, Cohen LA (1970) Concurrent general-acid and general-base catalysis of esterification. J Am Chem Soc 92:4377–4382CrossRefGoogle Scholar
  29. 29.
    Milstein S, Cohen LA (1970) Rate acceleration by stereopopulation control: models for enzyme action. Proc Natl Acad Sci USA 67:1143–1147CrossRefGoogle Scholar
  30. 30.
    Milstein S, Cohen LA (1972) Stereopopulation control. I. Rate enhancement in the lactonizations of o-hydroxyhydrocinnamic acids. J Am Chem Soc 94:9158–9165CrossRefGoogle Scholar
  31. 31.
    Menger FM, Ladika M (1990) Remote enzyme-coupled amine release. J Org Chem 35:3006–3007CrossRefGoogle Scholar
  32. 32.
    Menger FM, Ladika M (1988) Fast hydrolysis of an aliphatic amide at neutral pH and ambient temperature. A peptidase model. J Am Chem Soc 110:6794–6796CrossRefGoogle Scholar
  33. 33.
    Menger FM (1985) On the source of intramolecular and enzymatic reactivity. Acc Chem Res 18:128–134CrossRefGoogle Scholar
  34. 34.
    Menger FM, Chow JF, Kaiserman H, Vasquez PC (1983) Directionality of proton transfer in solution. Three systems of known angularity. J Am Chem Soc 105:4996–5002CrossRefGoogle Scholar
  35. 35.
    Menger FM (1983) Directionality of organic reactions in solution. Tetrahedron 39:1013–1040CrossRefGoogle Scholar
  36. 36.
    Menger FM, Grosssman J, Liotta DC (1983) Transition-state pliability in nitrogen-to-nitrogen proton transfer. J Org Chem 48:905–907CrossRefGoogle Scholar
  37. 37.
    Menger FM, Galloway AL, Musaev DG (2003) Relationship between rate and distance. Chem Commun 2370–2371Google Scholar
  38. 38.
    Menger FM (2005) An alternative view of enzyme catalysis. Pure Appl Chem 77:1873–1876, and references thereinCrossRefGoogle Scholar
  39. 39.
    Bruice TC, Pandit UK (1960) The effect of geminal substitution ring size and rotamer distribution on the intramolecular nucleophilic catalysis of the hydrolysis of monophenyl esters of dibasic acids and the solvolysis of the intermediate anhydrides. J Am Chem Soc 82:5858–5865CrossRefGoogle Scholar
  40. 40.
    Bruice TC, Pandit UK (1960) Intramolecular models depicting the kinetic importance of “Fit” in enzymatic catalysis. Proc Natl Acad Sci USA 46:402–404CrossRefGoogle Scholar
  41. 41.
    Brown RF, van Gulick NM (1956) The geminal alkyl effect on the rates of ring closure of bromobutylamines. J Org Chem 21:1046–1049CrossRefGoogle Scholar
  42. 42.
    Galli C, Mandolini L (2000) The role of ring strain on the ease of ring closure of bifunctional chain molecules. Eur J Org Chem 3117–3125 and references thereinGoogle Scholar
  43. 43.
    Kirby AJ, Parkinson A (1994) Most efficient intramolecular general acid catalysis of acetal hydrolysis by the carboxyl group. J Chem Soc Chem Commun 707–708Google Scholar
  44. 44.
    Brown CJ, Kirby AJ (1997) Efficiency of proton transfer catalysis. Intramolecular general acid catalysis of the hydrolysis of dialkyl acetals of benzaldehyde. J Chem Soc Perkin Trans 2:1081–1093Google Scholar
  45. 45.
    Craze G-A, Kirby AJ (1974) The hydrolysis of substituted 2-methoxymethoxybenzoic acids. J Chem Soc Perkin Trans 2:61–66Google Scholar
  46. 46.
    Barber SE, Dean KES, Kirby AJ (1999) A mechanism for efficient proton-transfer catalysis. Intramolecular general acid catalysis of the hydrolysis of 1-arylethyl ethers of salicylic acid. Can J Chem 792–801Google Scholar
  47. 47.
    Kirby AJ, de Silva MF, Lima D, Roussev CD, Nome F (2006) Efficient intramolecular general acid catalysis of nucleophilic attack on a phosphodiester. J Am Chem Soc 128:16944–16952CrossRefGoogle Scholar
  48. 48.
    Kirby AJ, Williams NH (1994) Efficient intramolecular general acid catalysis of enol ether hydrolysis. Hydrogen-bonding stabilization of the transition state for proton transfer to carbon. J Chem Soc Perkin Trans 2:643–648Google Scholar
  49. 49.
    Kirby AJ, Williams NH (1991) Efficient intramolecular general acid catalysis of vinyl ether hydrolysis by the neighbouring carboxylic acid group. J Chem Soc Chem Commun 1643–1644Google Scholar
  50. 50.
    Hartwell E, Hodgson DRW, Kirby AJ (2000) Exploring the limits of efficiency of proton-transfer catalysis in models and enzymes. J Am Chem Soc 122:9326–9327CrossRefGoogle Scholar
  51. 51.
    Kirby AJ (1997) Efficiency of proton transfer catalysis in models and enzymes. Acc Chem Res 30:290–296CrossRefGoogle Scholar
  52. 52.
    Asaad N, Davies JE, Hodgson DRW, Kirby AJ (2005) The search for efficient intramolecular proton transfer from carbon: the kinetically silent intramolecular general base-catalysed elimination reaction of o-phenyl 8-dimethylamino-1-naphthaldoximes. J Phys Org Chem 18:101–109CrossRefGoogle Scholar
  53. 53.
  54. 54.
    Casewit CJ, Colwell KS, Rappe AK (1992) Application of a universal force field to main group compounds. J Am Chem Soc 114:10046–10053CrossRefGoogle Scholar
  55. 55.
    Murrell JN, Laidler KJ (1968) Symmetries of activated complexes. Trans Faraday Soc 64:371–377CrossRefGoogle Scholar
  56. 56.
    Muller K (1980) Reaction paths on multidimensional energy hypersurfaces. Angew Chem Int Ed Engl 19:1–13CrossRefGoogle Scholar
  57. 57.
    Cancès MT, Mennucci B, Tomasi J (1997) A new integral equation formalism for the polarizable continuum model: theoretical background and applications to isotropic and anisotropic dielectrics. J Chem Phys 107:3032–3041CrossRefGoogle Scholar
  58. 58.
    Mennucci B, Tomasi J (1997) Coninuum solvation models: a new approach to the problem of solute’s charge distribution and cavity boundaries. J Chem Phys 106:5151–5158CrossRefGoogle Scholar
  59. 59.
    Mennucci B, Cancès MT, Tomasi J (1997) Evaluation of solvent effects in isotropic and anisotropic dielectrics and in ionic solutions with a unified integral equation method: theoretical bases, computational implementation, and numerical applications. J Phys Chem B 101:10506–10517CrossRefGoogle Scholar
  60. 60.
    Tomasi J, Mennucci B, Cancès MT (1997) The IEF version of the PCM solvation method: an overview of a new method addressed to study molecular solutes at the QM ab initio level. J Mol Struct THEOCHEM 464:211–226CrossRefGoogle Scholar
  61. 61.
    Fife TH, Przystas TJ (1979) Intramolecular general acid catalysis in the hydrolysis of acetals with aliphatic alcohol leaving groups. J Am Chem Soc 101:1202–1210CrossRefGoogle Scholar
  62. 62.
    Kirby AJ (2005) Effective molarities for intramolecular reactions. J Phys Org Chem 18:101–278CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Faculty of PharmacyAl-Quds UniversityJerusalemPalestine
  2. 2.Department of Chemistry and Chemical TechnologyAl-Quds UniversityJerusalemPalestine

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