VolSurf metabolic stability model

Figure 8.6 shows the projection of 1346 compounds from Johnson Johnson on the VolSurf metabolic stability model. The projected compounds are color-coded according to their percentage experimental metabolic stability (%MS) the red color defines compounds with %MS > 95, while the blue color defines compounds with %MS < 40. The figure shows that the great majority of projected compounds with %MS > 95 are predicted to be of medium or high stability for the metabolic activity of the CYP3A4, while compounds with low %MS < 40 are predicted to be unstable. The presence of outliers may be explained by the fact that the experimental %MS of the test set compounds is obtained from the activity of all CYP family enzymes (2C9, 3A4, 2D6 etc.), while the model uses only 3A4 mediated information. 

Figure 8.6. Proiection of 1346 compounds from Johnson, Johnson on the 2D PLS scores plot of the VolSurf metabolic stability model (open grey points). The black line discriminates between unstable and stable compounds in the metabolic stability model projected compounds on the left of the black line are predicted as unstable (%MS < 40), while...

In the following section, the calculation of the VolSurf parameters from GRID interaction energies will be explained and the physico-chemical relevance of these novel descriptors demonstrated by correlation with measured absorption/ distribution/metabolism/elimination (ADME) properties. The applications will be shown by correlating 3D molecular structures with Caco-2 cell permeabilities, thermodynamic solubilities and metabolic stabilities. Special emphasis will be placed on interpretation of the models by multivariate statistics, because a rational design to improve molecular properties is critically dependent on an understanding of how molecular features influence physico-chemical and ADME properties. 

A simple protocol was used to build the compounds compounds were modeled with the corresponding net charges, after which 2D-3D structure conversion was carried out using the program Concord [21]. The 3D dataset obtained was submitted to the VolSurf program, and principal component analysis (PCA) was applied for chemometric interpretation. No metabolic stability information was applied to the model. 

In the following we describe successful applications of the updated VolSurf software in modeling physicochemical and pharmacokinetic drug properties, comprising aqueous solubility, octanol/water partition coefficients, volume of distribution, and metabolic stability. 

In addition to the VolSurf treatment of the GRID fields, the information from the MIF can also be transformed to obtain a pharmacophoric type of representation, which is useful in the modeling of metabolic stability, cytochrome inhibition or even the direct study of the ADME related proteins (Fig. 10.3). The Almond software [17] transforms the MIF into a distance-based representation of the molecule interaction. These parameters describe the geometry of the interaction and QSAR models can be derived where the interaction with a protein is essential. Detailed information on these descriptors is presented elsewhere in this book. 

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