Polar surface area models

More recently the H-bonding potential (an estimate of hydrophilicity) and surface charge characteristics of a molecule have been used as predictors of passive Pm and intestinal absorption [17, 18], Theoretical models based on the determination of polar surface area (PSA) have been utilised to reasonable... 

Several in silica models for prediction of oral absorption are available [133-136]. Simple models are based on only few descriptors like logP, logD, or polar surface area (PSA), while they are only applicable if the compounds are passively absorbed. In case of absorption via active transporters or if efflux is involved, prediction of absorption is still not successful. 

The legacy aqueous thermodynamic solubility model is an in-house linear regression model consisting of 11 calculated descriptors which include cLogP and polar surface area. This is the model that was used to shape the property profile of the virtual products. This model has now been superseded by a Cubist (48) thermodynamic solubility model (R2 =... 

These model compound studies provide us with estimates of the first two fundamental parameters of ACp ap = 0.45 cal K-1 (mol A2)-1 of buried apolar surface area and ACPjpoi = — 14.3 cal K-1 moT1 of hydrogen bonds. The average polar surface area buried per hydrogen bond in globular proteins is 54 7 A2 (see below) so that ACp>poj = - 0.26 cal K-1 (mol A2)-1 of buried polar surface. 

Nitrofiiranyl derivatives 95 CoMFA and CoMSIA Tested with a set of 15 molecules. CoMFA (R2 = 0.78) outperformed CoMSIA. c Log P and polar surface area or steric bulk did not improve the models Hevener et al. (43)... 

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. 

Novartis uses the In Silico Profiling web tool. Available properties include the octanol water partition coefficient log P, molar refractivity, flexibility index, hydrogen bonding characteristics and molecular polar surface area. Various drug properties, such as intestinal absorption, BBB permeability or Plasma Protein Binding (PPB) are calculated based on in-house models. 

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