Hydrophobic descriptor

Hydrophobicity plays such an important role in drug absorption and distribution that it will be addressed in some depth. In combination with other relevant electronic, topological, steiic and hydrogen bond descriptors, hydrophobicity wields an important role in absorption, distribution, metabolism, elimination and toxicity (ADMET) phenomena. 

The equations were developed using several descriptors hydrophobicity (tt), electronegativity (a), molar refractivity (mr), steric terms (B1-B5), H-bond donor (Hbond do) and indicator variables (I, N) for ortho (O) and para (p/P) positions of the X- and Y-substituted benzene ring (62). The positive and negative coefficient of parameters, respectively, shows the positive and negative effect to the biological activity (C) with acceptable statistical range (R ... 

Two other atomic properties have been used in the definition of atom type, thereby increasing its fuzziness relative to that in the ap and tt descriptors - atomic log P contribution (yielding hydrophobic pairs, hps, and torsions, hts) and partial atomic charges (charge pairs, cps, and charge torsions, cts). 

Besides the aforementioned descriptors, grid-based methods are frequently used in the field of QSAR quantitative structure-activity relationships) [50]. A molecule is placed in a box and for an orthogonal grid of points the interaction energy values between this molecule and another small molecule, such as water, are calculated. The grid map thus obtained characterizes the molecular shape, charge distribution, and hydrophobicity. 

The most widely used descriptor for the hydrophobicity term in toxicology is the distribution coefficient between octanol and water, log Pq< - (the environmental scientists would rather call it log The bulk solvent octanol is of course a... 

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). 

The descriptors used should not be highly collinear with each other, for two reasons. First, this can lead to statistical instability and overprediction, and second, collinearity makes mechanistic interpretation difficult. For example, Cronin and Schultz [41] have pointed out that although a good correlation could be obtained between the skin sensitization potential and the hydrophobicity of a series of bromoalkanes, a correlation between skin sensitization potential and molecular weight had exactly the same statistics, because hydrophobicity and molecular weight are very highly correlated in homologous series. 

Cronin, M.T.D., Deardon, J.C., Duffy, J.C. et al. (2002) The Importance of Hydrophobicity and Electrophilicity Descriptors in Mechanistically-Based QSARs for Toxicological Endpoints. SAR and QSAR in Environmental Research, 13(1), 167-176. 

A comparahve analysis of coefficients and descriptors clarifies the relationship between lipophilicity and hydrophobicity (Y in Eq. 4 is the molar volume which assesses the solute s capacity to elicit nonpolar interactions (i.e. hydrophobic forces) which, as also clearly stated in the International Union of Pure and Applied Chemistry definitions [3] are not synonyms but, when only neutral species are concerned, may be considered as interchangeable. In the majority of partitioning systems, the lipophilicity is chiefly due to the hydrophobicity, as is clearly indicated by the finding that the product of numerical values of the descriptors V and of the coefficient v is larger in absolute value than the corresponding product of other couples of descriptors/coefficients [9]. This explains the very common linear rela-... 

Valko et al. [37] developed a fast-gradient RP-HPLC method for the determination of a chromatographic hydrophobicity index (CHI). An octadecylsilane (ODS) column and 50 mM aqueous ammonium acetate (pH 7.4) mobile phase with acetonitrile as an organic modifier (0-100%) were used. The system calibration and quality control were performed periodically by measuring retention for 10 standards unionized at pH 7.4. The CHI could then be used as an independent measure of hydrophobicity. In addition, its correlation with linear free-energy parameters explained some molecular descriptors, including H-bond basicity/ acidity and dipolarity/polarizability. It is noted [27] that there are significant differences between CHI values and octanol-water log D values. 

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). 

Thus, a molecule can be characterized in terms of its potential hydrogen bonding, polar, hydrophobic and ionic interactions in 3D space. The size and the spatial distribution of these molecular interaction contours is translated into a quantitative scheme, the VolSurf descriptors, without the need to align the molecules in 3D space [8, 9] (Fig. 17.1). 

The molecular descriptors refer to the molecular size and shape, to the size and shape of hydrophilic and hydrophobic regions, and to the balance between them. Hydrogen bonding, amphiphilic moments, critical packing parameters are other useful descriptors. The VolSurf descriptors have been presented and explained in detail elsewhere [8]. The VolSurf descriptors encode physico-chemical properties and, therefore, allow both for a design in the physico-chemical property space in order to rationally modulate pharmacokinetic properties, and for establishing quantitative structure-property relationships (QSPR). 

Calculated molecular properties from 3D molecular fields of interaction energies are a novel approach to correlate 3D molecular structures with pharmacodynamic, pharmacokinetic and physico-chemical properties. The novel VolSurf descriptors quantitatively characterize size, shape, polarity, hydrophobicity and the balance between them. 

In the multimedia models used in this series of volumes, an air-water partition coefficient KAW or Henry s law constant (H) is required and is calculated from the ratio of the pure substance vapor pressure and aqueous solubility. This method is widely used for hydrophobic chemicals but is inappropriate for water-miscible chemicals for which no solubility can be measured. Examples are the lower alcohols, acids, amines and ketones. There are reported calculated or pseudo-solubilities that have been derived from QSPR correlations with molecular descriptors for alcohols, aldehydes and amines (by Leahy 1986 Kamlet et al. 1987, 1988 and Nirmalakhandan and Speece 1988a,b). The obvious option is to input the H or KAW directly. If the chemical s activity coefficient y in water is known, then H can be estimated as vwyP[>where vw is the molar volume of water and Pf is the liquid vapor pressure. Since H can be regarded as P[IC[, where Cjs is the solubility, it is apparent that (l/vwy) is a pseudo-solubility. Correlations and measurements of y are available in the physical-chemical literature. For example, if y is 5.0, the pseudo-solubility is 11100 mol/m3 since the molar volume of water vw is 18 x 10-6 m3/mol or 18 cm3/mol. Chemicals with y less than about 20 are usually miscible in water. If the liquid vapor pressure in this case is 1000 Pa, H will be 1000/11100 or 0.090 Pa m3/mol and KAW will be H/RT or 3.6 x 10 5 at 25°C. Alternatively, if H or KAW is known, C[ can be calculated. It is possible to apply existing models to hydrophilic chemicals if this pseudo-solubility is calculated from the activity coefficient or from a known H (i.e., Cjs, P[/H or P[ or KAW RT). This approach is used here. In the fugacity model illustrations all pseudo-solubilities are so designated and should not be regarded as real, experimentally accessible quantities. 

The octanol-water partition coefficient Kow is widely used as a descriptor of hydrophobicity. Variation in /fow is primarily attributable to variation in activity coefficient in the aqueous phase (Miller et al. 1985) thus, the same correlations used for solubility in water are applicable to /fow. Most widely used is the Hansch-Leo compilation of data (Leo et al. 1971, Hansch and Leo 1979) and related predictive methods. Examples of Kow correlations are ... 

The octanol-water partition coefficient, Kow, is the most widely used descriptor of hydrophobicity in quantitative structure activity relationships (QSAR), which are used to describe sorption to organic matter, soil, and sediments [15], bioaccumulation [104], and toxicity [105 107J. Octanol is an amphiphilic bulk solvent with a molar volume of 0.12 dm3 mol when saturated with water. In the octanol-water system, octanol contains 2.3 mol dm 3 of water (one molecule of water per four molecules of octanol) and water is saturated with 4.5 x 10-3 mol dm 3 octanol. Octanol is more suitable than any other solvent system (for) mimicking biological membranes and organic matter properties, because it contains an aliphatic alkyl chain for pure van der Waals interactions plus the alcohol group, which can act as a hydrogen donor and acceptor. 

The separation of substituted benzene derivatives on a reversed-phase C-18 column has been examined [78]. The correlations between the logarithm of the capacity factor and several descriptors for the molecular size and shape and the physical properties of a solute were determined. The results indicated that hydrophobicity is the dominant factor to control the retention of substituted benzenes. Their retention in reversed-phase HPLC can be predicted with the help of the equations derived by multicombination of the parameters. 

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