Journal of Molecular Modeling

, Volume 18, Issue 1, pp 103–114

Computer-assisted design for paracetamol masking bitter taste prodrugs

Authors

  • Hatem Hejaz
    • Faculty of PharmacyAl-Quds University
    • Faculty of PharmacyAl-Quds University
  • Mustafa Khamis
    • Department of Chemistry and Chemical TechnologyAl-Quds University
Original Paper

DOI: 10.1007/s00894-011-1040-5

Cite this article as:
Hejaz, H., Karaman, R. & Khamis, M. J Mol Model (2012) 18: 103. doi:10.1007/s00894-011-1040-5

Abstract

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.

https://static-content.springer.com/image/art%3A10.1007%2Fs00894-011-1040-5/MediaObjects/894_2011_1040_Figa_HTML.gif
Figure

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

Keywords

DFT calculationsKirby’s enzyme modelsMasking bitter tasteParacetamol prodrugsProton transfer reaction

Supplementary material

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

Copyright information

© Springer-Verlag 2011