A reliable and efficient first principles-based method for predicting pKa values. 4. Organic bases.

The ionization (dissociation) constant (pK(a)) 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 pK(a) value(s) for a drug candidate is very important, especially in the early stages of drug discovery, as calculations are much cheaper than determining pK(a) values experimentally. In this study, we derive two linear fitting equations (pK(a) = a × ΔE + b; where a and b are constants and ΔE is the energy difference between the cationic and neutral forms, i.e., ΔE = E(neutral) -E(cationic)) for predicting pK(a) s 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 pK(a) units, respectively. Over 60% and 86% of the computed pK(a) values lie within ±0.5 and ±1.0 pK(a) units, respectively, of the corresponding experimental values. The results further demonstrate that our protocol is reliable and can accurately predict pK(a) values for organic bases.