A reliable and efficient first principles‐based method for predicting p K a values. 4. organic bases

The ionization (dissociation) constant (p K 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 p K 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 p K a values experimentally. In this study, we derive two linear fitting equations (p K a = a × Δ E + b; where a and b are constants and Δ E is the energy difference between the cationic and neutral forms, i.e., Δ E = E neutral − E cationic ) for predicting p K 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 p K a units, respectively. Over 60% and 86% of the computed p K a values lie within ±0.5 and ±1.0 p K a units, respectively, of the corresponding experimental values. The results further demonstrate that our protocol is reliable and can accurately predict p K a values for organic bases. © 2012 Wiley Periodicals, Inc.