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对于弱酸和弱碱化合物,解离常数(p Ka)是最重要的理化性质参数之一,其决定化合物的溶解度、亲脂性、生物富集性、毒性以及药物分子的吸收、分布、代谢和排泄(ADME)性质.通过实验方法测定化合物水溶液中的p Ka受到物质稳定性、仪器测定范围以及人力物力消耗等多方面的限制,因此过去几十年间发展了大量的p Ka预测方法.本文以有机小分子化合物为研究对象,回顾了20年来p Ka预测的研究成果,包括pK a实验数据的来源、质量、测定方法,重点介绍3类预测方法(线性自由能关系模型、定量结构-性质关系模型和第一性原理方法),并简单总结了常用的商业软件,最后提出未来p Ka预测研究需要关注的问题.
For weakly acidic and weakly basic compounds, the dissociation constant (p Ka) is one of the most important parameters of physicochemical properties which determines the solubility, lipophilicity, bioaccumulation, toxicity of the compound and the absorption, distribution, metabolism and excretion of the drug molecule (ADME) .A large number of p Ka prediction methods have been developed over the past few decades through experimental methods to determine the p Ka of the aqueous solution of compounds by various factors such as material stability, instrumentation range, and manpower and material resources consumption.In this paper, Small molecular compounds were reviewed. The results of p Ka predictions over the past 20 years were reviewed. The sources, qualities and determination methods of pKa data were reviewed. Three types of prediction methods (linear free energy model, quantitative structure-property relationship model And the first principle method), and briefly summarizes the commonly used commercial software, finally put forward the future p Ka prediction research needs attention.