Neutral descriptor values

A, B and V are constant for a given solute (Eig. 12.4 shows the value of A, 0.78, for atenolol). This means that the balance between intermolecular forces varies with the system investigated as would be expected from a careful reading of Section 12.1.1.3. This can also be demonstrated by using a completely different approach to factorize log P, i.e. a computational method based on molecular interaction fields [10]. Volsurf descriptors [11] have been used to calculate log P of neutral species both in n-octanol-water and in alkane-water [10]. 

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-... 

Descriptor vsa base represents van der Waals surface area of basic atoms and indicates the basicity of a compound. Under physiological conditions, a compound with a high vsa base value tends to be protonated and carries positive charges. The positive contribution to log PS indicated that basicity facilitates the compound s permeability across the BBB. This was consistent with their observation that basic compounds have higher log PS values than neutral and acidic compounds. 

Examples of structure-resorption correlations using octanol-water partition coefficients as descriptors have been published and are discussed here using several examples. These correlations with log Poet. are generally useful. This is especially true as long as neutral drugs are involved, but values often are imprecise in case of charged drugs. 

The set of 51 benzamidine-based thrombin inhibitors was taken from the study of Sugano et al. (2000). Experimental rat everted sac permeabilities were expressed as log(ES A) values.2 The experimental permeability in this assay is expressed as ratio of outer (mucosal side) concentration of the drug and inner (serosal side) concentration after 1 h incubation of the everted sac of rat small intestine. All molecules were treated in their neutral form and converted into their 3D structures using CORINA (Sadowski et al. 1992). From GRID molecular interaction fields for water, dry, and carbonyl oxygen probes, a set of 72 VolSurf descriptors (Cruciani et al. 2000) was computed and analysed as described above. 

The great difference in slopes for short-bridged peptides between the two systems can be rationalized in terms of differences in the nuclear part of the p descriptor. In the charged metallo systems with n = 1-3 prolines, the rates of intra-molecular electron transfer decrease rapidly by about 3 orders of magnitude. For these systems, the LRET mechanism is largely under the control of the nuclear factor (Pn = 9.5 nm" and Pei = 6.5 nm ) (10). The much smaller distance dependence of fcet in the Trp -Tyr system for peptides with n = 0-2, associated largely with the TS pathway and weak nuclear control, is consistent with the neutral character of the Tip and Tyr radicals involved in LRET and, thus, the low value of Xout (3). 

Luan et al. (2005PR1454) developed QSPR models to predict the pK, values of a set of 74 neutral and basic drugs via hnear and nonlinear methods. A CODESSA approach was used to derive descriptors and to build linear models RBFNN was used to generate the nonlinear models. Both models used the same descriptors selected by the heuristic method (HM) the descriptors accounted for the relative nitrogen content and polarizabUity of the compounds related to the ease of protonation of the molecules. The results were fair in view of the complexity and relatively large size of the drug molecules (R > 0.6—0.7). 

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