Abraham descriptors

Human intestinal absorption of 5 (01JPS749) and 6 (01MI30) was predicted by using five Abraham descriptors and CaCo-2 monolayer, respectively. The effect of hydrophobicity and molecular mass on the accumulation of 10 fluoroquinolones, including 5, by Staphylococcus aureus were evaluated (01MI14). 

C. N., Boutina, D., Beck, G., Sherbom, B., Cooper, J., Platts, J. A. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors. J. Pharm. Sci. 2001, 90, 749-784. 

Values calculated based on original and interpolated Abraham descriptors. Values in brackets are calculated based on Abraham parameters regressed from COSMO a-moments [65]. 

Barker, M. C., Box, K. J., Tam, K. Y. Calculation of Abraham descriptors from solvent-water partition coefficients in four different systems evaluation of different methods of calculation. J. 

In an excellent paper, Zhao et al. [29] assembled a carefully reviewed literature set of human absorption data on 241 drugs. They showed that a linear regression model built with 5 Abraham descriptors could fit percent human absorption data reasonably well (r2 = 0.83, RMSE = 14%). The descriptors are excess molar refraction (E), polarizability (S), hydrogen bond acidity (A), hydrogen bond basicity (B), and McGowan volume (V), all related to lipophilicity, hydrophilicity, and size. In a follow-on paper, data on rat absorption for 151 drugs was collected from the literature and modeled using the Abraham descriptors [30]. A model with only descriptors A and B had r2 = 0.66, RMSE = 15%. 

Zhao YH, Abraham MH, Hersey A and Luscombe CN (2003) Quantitative Relationship Between Rat Intestinal Absorption and Abraham Descriptors. Eur J Med Chem 38 pp 939-947. 

Zhao and coworkers [53] also constructed a linear model using the Abraham descriptors. The MLR model possesses good correlation and predictability for external data sets. In this equation, E is an excess molar refraction (cm3/mol/ 10.0) and S the dipolarity/polarizability, A and B are the hydrogen bond acidity and basicity, respectively, and V is the McGowan characteristic volume (cm3/ mol/100). The large coefficients of A and B indicate too polar molecules having poor absorption. 

Calculated descriptors have generally fallen into two broad categories those that seek to model an experimentally determined or physical descriptor (such as ClogP or CpKJ and those that are purely mathematical [such as the Kier and Hall connectivity indices (4)]. Not surprisingly, the latter category has been heavily populated over the years, so much so that QSAR/QSPR practitioners have had to rely on model validation procedures (such as leave-k-out cross-validation) to avoid models built upon chance correlation. Of course, such procedures are far less critical when very few descriptors are used (such as with the Hansch, Leo, and Abraham descriptors) it can even be argued that they are unnecessary. 

From a practical point of view, the use of Abraham descriptors appears to be preferable in cases where the experimentally derived solute descriptors of the compounds are well available for all solutes of interest. If partition coefficients between phases similar to those used for the derivation of the Abraham descriptors are considered, the Abraham approach is usually more accurate, because it only needs to predict the small differences from the experimental information intrinsically included in the descriptors, and it avoids the total prediction of the large free energy differences that often occur between different phases. On the other hand, the COSMO a-moment approach does not require experimental input for each individual solute, and hence can be applied even in cases where no experimental data are available for the solute or even when the solutes are still virtual candidates for drugs or other agents. Furthermore, the cr-moment approach is more rigorously derived from physical chemistry and provides more insight into the driving forces for partition equilibria. 

Baker et al. (1997) also used the Abraham descriptors to model Koc of a diverse data set, but with rather poor results ... 

While the majority of published models are based on a limited number of drug molecules, especially the study of Zhao et al. (2001) provides the most extensive compilation from available literature data and a statistical model derived from those using Abraham descriptors. We used this carefully selected dataset to build a quantitative model for human intestinal absorption employing VolSurf descriptors (see Cruciani et al. 2000). 

Evaluation ofhuman intestinal absorption data and subsequent derivation of a quantitative structure-activity (QSAR) with Abraham descriptors... 

Zhao et at, Journal of Pharmaceutical Sciences, 2002 Rate-limited steps of human oral absorption and QSAR studies 238 MLR, MNLR n.af Abraham descriptors (u — 5)... 

Zhao YH, LeJ, Abraham MH, Hersey A, Eddershaw PJ, Luscombe CN, Boutina D, Beck G, Sherborne B, Cooper J, and Platts JA. Evaluation of Human Intestinal Data and Subsequent Derivation of a Quantitative Structure-Activity Relationship (QSAR) with the Abraham Descriptors./P/tarro Sci 2001 90 749-784. 

---