A reliable and efficient first principles-based method for predicting pKa values. 4. organic bases
by Zhang, S. M.
The ionization (dissociation) constant (pKa) is one of the most important properties of a drug molecule. It is reported that almost 68% of ionized drugs are weak bases. To be able to predict accurately the pKa value(s) for a drug candidate is very important, especially in the early stages of drug discovery, as calculations are much cheaper than determining pKa values experimentally. In this study, we derive two linear fitting equations (pKa = a x ?E + b; where a and b are constants and ?E is the energy difference between the cationic and neutral forms, i.e., ?E = Eneutral-Ecationic) for predicting pKas for organic bases in aqueous solution based on a training/test set of almost 500 compounds using our previously developed protocol (OLYP/6-311+G**//3-21G(d) with the the conductor-like screening model solvation model, water as solvent; see Zhang, Baker, Pulay, J. Phys. Chem. A 2010, 114, 432). One equation is for saturated bases such as aliphatic and cyclic amines, anilines, guanidines, imines, and amidines; the other is for unsaturated bases such as heterocyclic aromatic bases and their derivatives. The mean absolute deviations for saturated and unsaturated bases were 0.45 and 0.52 pKa units, respectively. Over 60% and 86% of the computed pKa values lie within +/- 0.5 and +/- 1.0 pKa units, respectively, of the corresponding experimental values. The results further demonstrate that our protocol is reliable and can accurately predict pKa values for organic bases.
- Journal
- Journal of Computational Chemistry
- Volume
- 33
- Issue
- 31
- Year
- 2012
- Start Page
- 2469-2482
- URL
- https://dx.doi.org/10.1002/jcc.23068
- ISBN/ISSN
- 1096-987X; 0192-8651
- DOI
- 10.1002/jcc.23068