title: Prediction of pKaValues for Druglike Molecules Using Semiempirical Quantum Chemical Methods.
abstract: Rapid yet accurate pKaprediction 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 pKavalues of 53 amine groups in 48 druglike compounds. The approach uses an isodesmic reaction where the pKavalue is computed relative to a chemically related reference compound for which the pKavalue 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 pKacalculations 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 pKaprediction method; otherwise PM3/SMD or AM1/SMD should be used. Thus, fast and relatively accurate pKaprediction for 100-1000s of druglike amines is feasible with the current setup and relatively modest computational resources.
authors.affiliation: Department of Chemistry, University of Copenhagen , 1165 Copenhagen, Denmark.
authors.forename: Jan H
authors.identifier: http://orcid.org/0000-0002-1465-1010
authors.initials: JH
authors.lastname: Jensen
authors.affiliation: Cambridge MedChem Consulting , CB22 4RN Cambridge, U.K.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Swain
authors.affiliation: Section of Biostructural Research, Department of Drug Design and Pharmacology, University of Copenhagen , 1165 Copenhagen, Denmark.
authors.forename: Lars
authors.identifier: http://orcid.org/0000-0002-7607-7130
authors.initials: L
authors.lastname: Olsen
mesh_terms: D000588:Amines / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D000588:Amines