Descriptors absorption

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). 

MW is often taken as the size descriptor of choice, while it is easy to calculate and is in the chemist s mind. However, other size and shape properties are equally simple to calculate, and may offer a better guide to estimate potential for permeability. Thus far no systematic work has been reported investigating this in detail. Cross-sectional area Ad obtained from surface activity measurements have been reported as a useful size descriptor to discriminate compounds which can access the brain (Ad<80A ) of those that are too large to cross the blood-brain barrier (BBB) [55]. Similar studies have been performed to define a cut-off for oral absorption [56]. 

At Novartis, so-called BioavailabiUty Radar Plots [44] are used to visually display the oral absorption potential of molecules. On these plots five important calculated descriptors (log P, molecular weight, PSA, number of rotatable bonds and water solubility score [45]) are displayed on the axes of a pentagonal radar plot and compared with predefined property limits (green area) which were determined by the analysis of marketed oral drugs. These plots provide an intuitive tool that displays multiple parameters as a single chart in a straightforward but informative way, providing visual feedback about the molecule s bioavailabiUty potential (Fig. 5.5). 

PSA is also used as H-bond descriptor to predict various properties of chemicals and drugs. PSA is defined as that part of a molecular surface that arises from oxygen and nitrogen atoms, and also the hydrogens attached to them. Applications of PSA as a QSAR descriptor in correlations with permeability and absorption were carried out first by Van de Waterbeemd et al. [30] and Palm et al. [31]. Clark [32-34] developed this further. Chapter 5 in this book is completely devoted to... 

A volume-related term (expressed by polarizability) and electrostatics (expressed by partial atomic charge) made minor contributions to intestinal absorption in humans. Lipophilicity, expressed by logP or logD values, shows no correlation with the human absorphon data. Recently, similar results were obtained for 154 passively transported drugs on the basis of surface thermodynamics descriptors [39] ... 

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. 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

In addition, the calculation of many different ID, 2D and 3D descriptors is possible using a range of commercially available software packages, such as Sybyl, Cerius2, Tsar, Molconn-Z and Hybot. Several new descriptor sets are based on quantification of 3D molecular surface properties, and these have been explored for the prediction of, e.g., Caco-2 permeability and oral absorption. It is pointed out here that a number of these new descriptors are strongly correlated to the more traditional physico-chemical properties. 

Molecules with a large molecular weight or size are confined to the transcellular route and its requirements related to the hydrophobicity of the molecule. The transcellular pathway has been evaluated for many years and is thought to be the main route of absorption of many drugs, both with respect to carrier-mediated transport and passive diffusion. The most well-known requirement for the passive part of this route is hydrophobicity, and a relationship between permeability coefficients across cell monolayers such as the Caco-2 versus log P and log D 7.4 or 6.5 have been established [102, 117]. However, this relationship appears to be nonlinear and reaches a plateau at around log P of 2, while higher lipophilicities result in reduced permeability [102, 117, 118]. Because of this, much more attention has recently been paid towards molecular descriptors other than lipophilicity [86, 119-125] (see section 5.5.6.). The relative contribution between the para-cellular and transcellular components has also been evaluated using Caco-2 cells, and for a variety of compounds with different charges [110, 112] and sizes [112] (see Section 5.4.5). 

Another possible advantage with MolSurf descriptors (and also other multi parameter descriptors) is the fact that they describe the investigated compounds not only with a single value, as in the case of PSA and log P descriptors, but in a multivariate way. This approach provides a more balanced description of the requirements that a structure must have in order to be well absorbed and may, in turn, provide additional insight on how to develop compounds having favorable absorption properties. However, as will be described in Section 16.4.10, simpler -i.e., less computationally demanding - parameters carrying similar information content with equal interpretability may be used to derive models for intestinal absorption at the same level of statistical quality. 

Another set of useful 3D-based descriptors for predicting intestinal absorption is through the use of the GRID program. Applications of these descriptors are discussed in Chapter 4. 

The sum of hydrogen bonding donor and acceptor related E-state descriptors are well correlated with the corresponding HYBOT parameters, with r2-values of 0.8-0.95 [38]. This gives the E-state descriptors a link to experimental values, which is positive but not necessary for the purpose of generating useful models with good statistical quality for, in this case, intestinal absorption. 

Partial least squares (PLS) projections to latent structures [40] is a multivariate data analysis tool that has gained much attention during past decade, especially after introduction of the 3D-QSAR method CoMFA [41]. PLS is a projection technique that uses latent variables (linear combinations of the original variables) to construct multidimensional projections while focusing on explaining as much as possible of the information in the dependent variable (in this case intestinal absorption) and not among the descriptors used to describe the compounds under investigation (the independent variables). PLS differs from MLR in a number of ways (apart from point 1 in Section 16.5.1) ... 

Agatonovic-Kustrin, S., Bereseord, R., Yusoe, A. P. M., Theoretically-derived molecular descriptors important in human intestinal absorption, J. Pharm. Biomed. Anal. 

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. 

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