VolSurf oral absorption

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. 

VolSurfwas initially validated on oral absorption [16, 17] and blood-brain-barrier permeation [18] models (see belovi ). VolSurf has continued to be developed to improve in silico predictions for ADME properties, although its use has also been extended to receptor-based evaluation of binding affinity [19, 20], While other soft-ivare tools for ADME modeling are available (see, e.g., [21]), the MIF-based collection of sofhvare and models available from Molecular Discovery (MD) is both extensive and ivell validated by the private sector. Three programs from MD, VolSurf, MetaSite and Almond, are particularly suited for rapid evaluation of large compound sets [22] in connection ivith ADME/Tox related properties ... 

Fig. 14.12 VolSurf model to correlate 49 matrix metalloproteinase inhibitors with different zinc-binding functionalities to rabbit oral bioavailability for metabolically stable compounds. (A) Semiquantitative PLS model 0.424, r 0.646, 4 PLS components) to rank novel synthesis candidates. Main factors influencing absorption, that is, lower polarity, capacity factors and increased hydrophobicity, are in agreement with global models for human intestinal absorption. (B) Distribution of polar and hydrophobic surfaces for two molecules with low (0981) and higher (2290) rabbit AUC from oral pharmacokinetic studies.

Fig. 3. Correlation of VolSurf descriptors with human intestinal absorption using multivariate statistics (PLS) based on 20 drug molecules as reported by Cuba et al. (2000). The PLS plot (ul versus tl) and the corresponding PLS coefficient plot is shown. Different interaction pattern with the GRID water probe are displayed for the orally available nordiazepam (left) versus the large area for the non-available...

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