Global ADME Models for Intestinal Absorption and Protein Binding

Global ADME Models for Intestinal Absorption and Protein Binding 

This section will provide an overview on ADME models from our group to illustrate our approach for building predictive models on structurally diverse training sets. Datasets for intestinal human absorption and human serum albumin binding are discussed, while models for other relevant ADME properties have also been obtained. Those models, however, do not stand alone but are used in combination with those models tailored for affinity and selectivity in the frame of multidimensional lead optimization. 

These descriptors have been reported in the literature to correlate with bioavailability, blood-brain partitioning, membrane transport and other properties [156-159]. They are also correlated to relevant physicochemical properties and were also successfully applied to many internal and public data. Eor example, we derived PLS models [160] using 72 VolSurf descriptors for human serum albumin (HSA) binding using 95 drugs on a 

This agrees to internal VolSurf models derived for PAMPA membrane transport [163] to understand passive transcellular transport across membranes. One of our internal models based on 29 compounds characterized by immobilized artificial membrane chromatography by Salminen etal. ]164] shows an of 0.81 and = 0.70 for two PLS components derived using VolSurf descriptors. This is one of the rare examples where ionized starting molecules led to slightly better PLS statistics, while the general chemical interpretation is not affected. 

VolSurf was also successfully applied in the literature to predict absorption properties [156] from experimental drug permeability data of 55 compounds [165] in Caco-2 cells (human intestinal epithelial cell line derived from a colorectal carcinoma) and MDCK cell monolayers (Madin-Darby canine kidney). In this interesting case, it was shown that models including counterions for charged molecules clearly show significantly better quality and overall performance. The final model was also able to correctly predict, to a great extent, the relative ranking of molecules from another Caco-2 permeability study by Yazdanian et al. ]166]. 

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