Assessment of tautomer distribution using the condensed reaction graph approach

• Published in: Journal of computer-aided molecular design 2018-03, Vol.32 (3), p.401-414
• Main Authors: Gimadiev, T. R., Madzhidov, T. I., Nugmanov, R. I., Baskin, I. I., Antipin, I. S., Varnek, A.
• Format: Article
• Language: English
• Subjects: Acidity; Animal Anatomy; Basicity; Chemical equilibrium; Chemical Sciences; Cheminformatics; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Computer Simulation; Equilibrium; Histology; Isomerism; Modelling; Molecular Structure; Morphology; Physical Chemistry; Quantitative Structure-Activity Relationship; Solvents; Solvents - chemistry; Support vector machines; Tautomers; Temperature; Test sets; Thermodynamics; Transformations; Water - chemistry
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-018-0101-6

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 (Q 2  = 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.