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Predicting the Prevalence of Alternative Warfarin Tautomers in Solution
- Source :
- Malde, A K, Stroet, M, Caron, B, Visscher, K M & Mark, A E 2018, ' Predicting the Prevalence of Alternative Warfarin Tautomers in Solution ', Journal of Chemical Theory and Computation, vol. 14, no. 8, pp. 4405-4415 . https://doi.org/10.1021/acs.jctc.8b00453, Journal of Chemical Theory and Computation, 14(8), 4405-4415. American Chemical Society
- Publication Year :
- 2018
- Publisher :
- American Chemical Society, 2018.
-
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.
- Subjects :
- Work (thermodynamics)
Thermodynamics
Molecular Dynamics Simulation
010402 general chemistry
01 natural sciences
symbols.namesake
Molecular dynamics
0103 physical sciences
Physical and Theoretical Chemistry
010304 chemical physics
Chemistry
Solvation
Anticoagulants
Water
Stereoisomerism
Tautomer
Standard enthalpy of formation
0104 chemical sciences
Computer Science Applications
Gibbs free energy
Solutions
Models, Chemical
Solvents
symbols
Racemic mixture
Warfarin
Enantiomer
Subjects
Details
- Language :
- English
- ISSN :
- 15499626 and 15499618
- Volume :
- 14
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Journal of Chemical Theory and Computation
- Accession number :
- edsair.doi.dedup.....db04a1478a8663b6c0dc0b1dd9d8c103