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Predicting pKa Values in Aqueous Solution for the Guanidine Functional Group from Gas Phase Ab Initio Bond Lengths

Authors

  • Mark Z. Griffiths,

    1. Manchester Institute of Biotechnology (MIB), 131 Princess Street, M1 7DN, GB
    2. School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, GB
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  • Ibon Alkorta,

    1. Instituto de Química Médica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain
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  • Paul L. A. Popelier

    Corresponding author
    1. Manchester Institute of Biotechnology (MIB), 131 Princess Street, M1 7DN, GB
    2. School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, GB
    • Manchester Institute of Biotechnology (MIB), 131 Princess Street, M1 7DN, GB
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Abstract

Here we applied a novel method1a to predict pKa values of the guanidine functional group, which is a notoriously difficult. This method, which was developed in our lab, uses only one ab initio bond length obtained at a low level of theory. The method is shown to work for drug molecules, delivers prediction errors of less than 0.5 log units, successfully treats tautomerisation in close relation with experiment, and demonstrates strong correlations with only a few data points. The high structural content of the ab initio bond length makes a given data set essentially divide itself into high correlation subsets. One then observes that molecules within a subset possess a common substructure. Each high correlation subset exists in its own region of chemical space. The high correlation subset method is explored with respect to this position in chemical space, in particular tautomerisation. The proposed method is able to distinguish between different tautomeric forms and the preferred tautomeric form emerges naturally, in agreement with experiment.

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