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

Abstract

Rapid yet accurate pK prediction for druglike molecules is a key challenge in computational chemistry. This study uses PM6-DH+/COSMO, PM6/COSMO, PM7/COSMO, PM3/COSMO, AM1/COSMO, PM3/SMD, AM1/SMD, and DFTB3/SMD to predict the pK values of 53 amine groups in 48 druglike compounds. The approach uses an isodesmic reaction where the pK value is computed relative to a chemically related reference compound for which the pK value has been measured experimentally or estimated using a standard empirical approach. The AM1- and PM3-based methods perform best with RMSE values of 1.4-1.6 pH units that have uncertainties of ±0.2-0.3 pH units, which make them statistically equivalent. However, for all but PM3/SMD and AM1/SMD the RMSEs are dominated by a single outlier, cefadroxil, caused by proton transfer in the zwitterionic protonation state. If this outlier is removed, the RMSE values for PM3/COSMO and AM1/COSMO drop to 1.0 ± 0.2 and 1.1 ± 0.3, whereas PM3/SMD and AM1/SMD remain at 1.5 ± 0.3 and 1.6 ± 0.3/0.4 pH units, making the COSMO-based predictions statistically better than the SMD-based predictions. For pK calculations where a zwitterionic state is not involved or proton transfer in a zwitterionic state is not observed, PM3/COSMO or AM1/COSMO is the best pK prediction method; otherwise PM3/SMD or AM1/SMD should be used. Thus, fast and relatively accurate pK prediction for 100-1000s of druglike amines is feasible with the current setup and relatively modest computational resources.

A Quantitative Structure-Property Relationship Model Based on Chaos-Enhanced Accelerated Particle Swarm Optimization Algorithm and Back Propagation Artificial Neural Network

“…Figure 5 Moreover, three artificial intelligence models, BP ANN, SVM, and PSO BP ANN, were selected as the comparison models. In addition, Jensen et al [50] used PM6, PM7, PM3, AM1, and DFTB3 methods to predict the pKa values of some amine groups and indicated that PM3/COSMO was the best pKa prediction method. Therefore, in order to verify the performance of the model, the PM3/COSMO model [50] was selected as the comparison model in the study.…”

“…The comprehensive performance of the model was verified by the prediction experiments of the pKa values of various compounds. The experimental database was obtained from References [50][51][52] and is shown in Table 1. Table S1 lists the compound families used for the QSPR modeling in this paper.…”

“…The testing set is used to test the performance of the model and the tested performance can directly reflect the comprehensive performance of the model. 11.00-13.80 [50,51] In this paper, 70% of the data are used for training. Both the verification set and testing set account for 15%.…”

Relative pKa of some anilinium derivatives in methanol, acetonitrile, and tetrahydrofurane solvents

“…Generally, one would like to use the thermodynamic cycle in order to calculate the approximate free energies of deprotonation in solution according to the isodesmic reaction. This reaction is also known as the relative p K a calculation reaction or the proton exchange reaction …”

“…This reaction is also known as the relative pK a calculation reaction or the proton exchange reaction. [30][31][32] Based on the isodesmic thermodynamic cycle, the deprotonation Gibbs free energy ΔG * sln can be calculated as in Equation (2):…”