The optimization of aqueous solubility is an important step along the route to bringing a new therapeutic to market. We describe the development of an empirical computational model to rank the pH-dependent aqueous solubility of drug candidates. The model consists of three core components to describe aqueous solubility. The first is a multivariate QSAR model for the prediction of the intrinsic solubility of the neutral solute. The second facet of the approach is the consideration of ionization using a predicted pKa and the Henderson-Hasselbalch equation. The third aspect of the model is a novel method for assessing the effects of crystal packing on solubility through a series of short molecular dynamics simulations of an actual or hypothetical small molecule crystal structure at escalating temperatures. The model also includes a Monte Carlo error function that considers the variability of each of the underlying components of the model to estimate the 90% confidence interval of estimation.
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Johnson et al. (2007) studied this question.
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