Prediction of pKa values using the PM6 semiempirical method

Abstract

The PM6 semiempirical method and the dispersion and hydrogen bond-corrected PM6-D3H+ method are used together with the SMD and COSMO continuum solvation models to predict pKa values of pyridines, alcohols, phenols, benzoic acids, carboxylic acids, and phenols using isodesmic reactions and compared to published ab initio results. The pKa values of pyridines, alcohols, phenols, and benzoic acids considered in this study can generally be predicted with PM6 and ab initio methods to within the same overall accuracy, with average mean absolute differences of 0.6 - 0.7 pH units. For carboxylic acids the accuracy (0.7 - 1.0 pH units) is also comparable to ab initio results if a single outlier is removed. For primary, secondary, and tertiary amines the accuracy is, respectively, similar (0.5 - 0.6), slightly worse (0.5 - 1.0), and worse (1.0 - 2.5), provided that di- and triethylamine are used as reference molecules for secondary and tertiary amines. When applied to a drug like molecule where an empirical pKa predictor exhibits a large (4.9 pH unit) error, we find that the errors for PM6-based predictions are roughly the same in magnitude but opposite in sign. As a result most of the PM6-based methods predict the correct protonation state at physiological pH, while the empirical predictor does not. The computational cost is around 2-5 minutes per conformer per core processor, making PM6-based pKa prediction computationally efficient enough to be used for high-throughput screening using on the order of 100 core processors.

Prediction of pKa Values for Druglike Molecules Using Semiempirical Quantum Chemical Methods

“…Semiempirical QM methods such as PM6 9 and DFTB3 10 are orders of magnitude faster than QM methods but retain a flexible and, in principle, more transferable QM description of the molecules. One of us recently co-authored a proof-of-concept study 11 demonstrating that semiemprical QM methods can be used together with isodesmic reactions to predict pKa values of small model systems with accuracies similar to QM methods for many functional groups. However, amines proved the most di cult due to the diverse chemical environment of the ionizable nitrogen atoms.…”