Computer-Assisted Design for Paracetamol Masking Bitter Taste Prodrugs
Date
2011-04-15
Authors
Hejaz, Hatem
Karaman, Rafik
Khamis, Mustafa
Journal Title
Journal ISSN
Volume Title
Publisher
Springer-Verlag
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.
Description
Keywords
DFT calculations , Kirby’s enzyme models , Masking bitter taste , Paracetamol prodrugs , Proton transfer reaction