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.
Original language | English |
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Pages (from-to) | 4405-4415 |
Number of pages | 11 |
Journal | Journal of Chemical Theory and Computation |
Volume | 14 |
Issue number | 8 |
Early online date | 12 Jul 2018 |
DOIs | |
Publication status | Published - 14 Aug 2018 |
Funding
*Phone: +61 7 336 54616. Fax: +61 7 336 53872. E-mail: a. [email protected] (A.K. Malde). *Phone: +61 7 336 54180. Fax: +61 7 336 53872. E-mail: a.e. [email protected] (A.E. Mark). ORCID Alpeshkumar K. Malde: 0000-0002-8181-1619 Alan E. Mark: 0000-0001-5880-4798 Funding This work was funded from the Australian Grants Commission (Discovery Grants DP130102153 and DP160103414) with the assistance of high-performance computing resources provided by through the National Computational Merit Allocation Scheme supported by the Australian Government (projects n63 and m72). Notes The authors declare no competing financial interest.
Funders | Funder number |
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Australian Government | m72 |
Australian Grants Commission | |
Australian Research Council | DP130102153, DP160103414 |