Group contribution models aqueous solubility

The group contribution method allows the approximate calculation of solubility by summing up fragmental values associated with substmctural units of the compounds (see Section 7.1). In a group contribution model, the aqueous solubility values are computed by Eq. (12), where log S is the logarithm of solubility, C is the number of occurrences of a substmctural group, i, in a molecule, and is the relative contribution of the fragment i. 

The accurate prediction of the aqueous solubility of drugs and drug-like compounds is much further away from a satisfactory solution because the existing QSAR- or group-contribution-based solubility prediction models exhibit quite limited predictive power for new drug classes. Why is it that the extremely important problem of the prediction of aqueous solubility much less solved than the prediction of less important partition coefficients The answer is that the development of prediction models for logarithmic partition coefficients is much simpler, because the molecule X under consideration only acts as a solute at infinite dilution in the two phases. Hence the task is only to calculate the free energy of... 

Duffythe group contribution approach of Klopman and the neural network model of Huuskonen. " The PCCHEM program used at the US Environmental Protection Agency (EPA) incorporates three different equations. All of them are similar to GSE but have different coefficients to predict aqueous solubility depending on the range of log P values. " Meylan and Howard used a database of 817 (RMSE = 0.62) compounds to derive a heuristic equation ... 

Fig. 14. Schematic depiction of selected physical and chemical events during fat digestion. The 1- and 3-ester linkages of triglyceride (upper left) are cleaved by lipase, forming 2-monoglyceride and fatty acid. These lipolytic products leave the oil-water interface and are dispersed in the aqueous phase as mixed bile acids-lipolytic product micelles. A proposed molecular arrangement of the bile acid-lipolytic product micelle is shown in cross-section this model is based on studies of the bile acid-lecithin micelle (65). In this model, the hydrophobic back of the bile acid molecule apposes the paraffinic chains of the lipolytic products, and the hydroxy groups of the bile acid molecule are toward the aqueous phase. The paraffin chains of the interior of the micelle are liquid, thus permitting other water-insoluble molecules such as cholesterol and fat-soluble vitamins to dissolve in the micelle. Indeed, the solvent capacity of the bile acid-lipolytic product micelle is contributed chiefly by the paraffin chains of the lipolytic products.

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