A Computational Model for the Prediction of Aqueous Solubility That Includes Crystal Packing, Intrinsic Solubility, and Ionization Effects

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• 作者：Stephen R. Johnson ; Xue-Qing Chen ; Denette Murphy ; Olafur Gudmundsson
• 刊名：Molecular Pharmaceutics
• 出版年：2007
• 出版时间：August 2007
• 年：2007
• 卷：4
• 期：4
• 页码：513 - 523
• 全文大小：228K
• 年卷期：v.4,no.4(August 2007)
• ISSN：1543-8392

文摘

The optimization of aqueous solubility is an important step along the route to bringinga new therapeutic to market. We describe the development of an empirical computational modelto rank the pH-dependent aqueous solubility of drug candidates. The model consists of threecore components to describe aqueous solubility. The first is a multivariate QSAR model for theprediction of the intrinsic solubility of the neutral solute. The second facet of the approach is theconsideration of ionization using a predicted pK_a and the Henderson-Hasselbalch equation.The third aspect of the model is a novel method for assessing the effects of crystal packing onsolubility through a series of short molecular dynamics simulations of an actual or hypotheticalsmall molecule crystal structure at escalating temperatures. The model also includes a MonteCarlo error function that considers the variability of each of the underlying components of themodel to estimate the 90% confidence interval of estimation.