Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, USA.
J Comput Chem. 2012 Dec 5;33(31):2469-82. doi: 10.1002/jcc.23068. Epub 2012 Jul 27.
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.
离解常数（pK(a)）是药物分子最重要的性质之一。据报道，约 68%的电离药物是弱碱。能够准确预测候选药物的 pK(a)值非常重要，尤其是在药物发现的早期阶段，因为计算比实验确定 pK(a)值便宜得多。在这项研究中，我们根据使用我们之前开发的方案（OLYP/6-311+G**//3-21G(d)，导体相似屏蔽模型溶剂化模型，溶剂为水；见 Zhang, Baker, Pulay, J. Phys. Chem. A 2010, 114, 432）对近 500 种化合物的训练/测试集，为预测水溶液中有机碱的 pK(a)值推导了两个线性拟合方程（pK(a) = a × ΔE + b；其中 a 和 b 是常数，ΔE 是阳离子和中性形式之间的能量差，即 ΔE = E(neutral) -E(cationic)）。一个方程适用于饱和碱，如脂肪族和环状胺、苯胺、胍、亚胺和脒；另一个方程适用于不饱和碱，如杂环芳基碱及其衍生物。饱和和不饱和碱的平均绝对偏差分别为 0.45 和 0.52 pK(a)单位。计算出的 pK(a)值中，有超过 60%和 86%分别在实验值的±0.5 和±1.0 pK(a)单位内。结果进一步表明，我们的方案可靠，可以准确预测有机碱的 pK(a)值。
