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Assessment of tautomer distribution using the condensed reaction graph approach

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Abstract

We report the first direct QSPR modeling of equilibrium constants of tautomeric transformations (logK T ) in different solvents and at different temperatures, which do not require intermediate assessment of acidity (basicity) constants for all tautomeric forms. The key step of the modeling consisted in the merging of two tautomers in one sole molecular graph (“condensed reaction graph”) which enables to compute molecular descriptors characterizing entire equilibrium. The support vector regression method was used to build the models. The training set consisted of 785 transformations belonging to 11 types of tautomeric reactions with equilibrium constants measured in different solvents and at different temperatures. The models obtained perform well both in cross-validation (Q2 = 0.81 RMSE = 0.7 logK T units) and on two external test sets. Benchmarking studies demonstrate that our models outperform results obtained with DFT B3LYP/6-311 ++ G(d,p) and ChemAxon Tautomerizer applicable only in water at room temperature.

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Acknowledgements

This study was supported by Russian Science Foundation, Grant No. 14-43-00024. TG thanks the IDEX UniStra program for the fellowship.

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Authors and Affiliations

  1. University of Strasbourg, 1 rue Blaise Pascal, 67000, Strasbourg, France

    T. R. Gimadiev & A. Varnek

  2. Kazan Federal University, 18 Kremlyovskaya Str., Kazan, Russian Federation, 420008

    T. R. Gimadiev, T. I. Madzhidov, R. I. Nugmanov, I. I. Baskin & I. S. Antipin

  3. Department of Physics, Moscow State University, Moscow, Russian Federation, 119991

    I. I. Baskin

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  1. T. R. Gimadiev
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  2. T. I. Madzhidov
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Correspondence to A. Varnek.

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Supporting Information

contains the parameters of the the best 10 SVR models selected for consensus calculation, outliers analysis, tautomeric transformations which couldn’t be generated using the ChemAxon tautomerization plugin, a technical information about CGR creation, SDF format for CGR storage and results of DFT calculations for external datasets. The training and two test datasets used in the modeling are available in the RDF format in Supporting Information. (DOCX 1542 KB)

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Gimadiev, T.R., Madzhidov, T.I., Nugmanov, R.I. et al. Assessment of tautomer distribution using the condensed reaction graph approach. J Comput Aided Mol Des 32, 401–414 (2018). https://doi.org/10.1007/s10822-018-0101-6

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