Predicting the Prevalence of Alternative Warfarin Tautomers in Solution.
J Chem Theory Comput
; 14(8): 4405-4415, 2018 Aug 14.
Article
en En
| MEDLINE
| ID: mdl-29999318
ABSTRACT
Warfarin, a widely used oral anticoagulant, is prescribed as a racemic mixture. Each enantiomer of neutral Warfarin can exist in 20 possible tautomeric states leading to complex pharmacokinetics and uncertainty as to the relevant species under different conditions. Here, the ability of alternative computational approaches to predict the preferred tautomeric form(s) of neutral Warfarin in different solvents is examined. It is shown that varying the method used to estimate the heat of formation in vacuum (direct or via homodesmic reactions), whether entropic corrections were included, and the method used to estimate the free enthalpy of solvation (i.e., PCM, COSMO, or SMD implicit models or explicit solvent) lead to large differences in the predicted rank and relative populations of the tautomers. In this case, only a combination of the enthalpy of formation using homodesmic reactions and explicit solvent to estimate the free enthalpy of solvation yielded results compatible with the available experimental data. The work also suggests that a small but significant subset of the possible Warfarin tautomers are likely to be physiologically relevant.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Warfarina
/
Anticoagulantes
Tipo de estudio:
Prevalence_studies
/
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
J Chem Theory Comput
Año:
2018
Tipo del documento:
Article
País de afiliación:
Australia