VolSurf parameters

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. 

PETRA (calculation of physicochemical parameters) Molecular Networks GmbH, Nagelsbachstrasse 25, D-91052 Erlangen, Germany http //www.mol-net.de/ VolSurf Molecular Discovery Ltd., West Way House, Elms Parade, Oxford 0X2 9LL, UK http //www.moldiscovery.com/... 

The molecular descriptors refer to the molecular size and shape, to the size and shape of hydrophilic and hydrophobic regions, and to the balance between them. Hydrogen bonding, amphiphilic moments, critical packing parameters are other useful descriptors. The VolSurf descriptors have been presented and explained in detail elsewhere [8]. The VolSurf descriptors encode physico-chemical properties and, therefore, allow both for a design in the physico-chemical property space in order to rationally modulate pharmacokinetic properties, and for establishing quantitative structure-property relationships (QSPR). 

Several papers have also been published in which a correlation has been sought between permeation across Caco-2 cells and physicochemical properties of the compounds. The review article by Ekins et al. (2000) discusses several studies to predict Caco-2 cell permeation. Correlations have been found with polar surface area, hydrogen bond descriptors, VolSurf, and other parameters. Van de Waterbeemd et al. (2001a) also discuss models for predicting oral absorption of compounds, including the use of Caco-2 cell lines. This paper also provides much useful information on the optimization of pharmacokinetic parameters in drug development. 

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. 

PAMPA-QSAR-VolSurf To evaiuate absorption of compounds across the membrane via a transceiiuiar route, the permeability of peptide derivatives and related compounds was measured by the PAMPA. The permeability coefficients by PAMPA were analyzed quantitatively using classical QSAR and VolSurf approaches with the physico-chemical parameters. The results from both approaches showed that hydrogen bonding ability of molecules in addition to hydrophobicity at a particular pH were significant in determining variations in PAMPA permeability coefficients. The relationship between Caco-2 cell permeability and artificial lipid membrane permeability was then determined. The compounds were sorted according to their absorption pathway in the plot of the Caco-2 cell and PAMPA permeability coefficients. 

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