Calculation from fragment contributions

Alternative approaches to the calculation of log P values from fragment contributions comprise solvent regression equations - extrapolations from... 

When looking at Figure 8, it is obvious that the nature of the solvent has an infiuence on the activity of the enzyme, even when the hydration of the enzyme is maintained constant by working at a fixed water activity. The parameter most frequently used to relate the nature of the solvent to its effect on enzyme-catalyzed reactions is log P, where P is the partition coefficient of the solvent between 1-octanol and water. This parameter, quantifying the hydrophobicity of organic molecules, can, of course, be measured experimentally, but it can also be calculated from group contribution methods, such as the hydrophobic fragmental content (44). 

In the present case, each endpoint involves—in addition to the fully interacting solute—an intact side chain fragment without any interactions with its environment. This fragment is equivalent to a molecule in the gas phase (acetamide or acetate) and contributes an additional term to the overall free energy that is easily calculated from ideal gas statistical mechanics [18]. This contribution is similar but not identical at the two endpoints. However, the corresponding contributions are the same for the transfonnation in solution and in complex with the protein therefore, they cancel exactly when the upper and lower legs of the thermodynamic cycle are subtracted (Fig. 3a). 

Nitrogen (as 15N) and oxygen (as 170) also contribute to (M + 1)+, if present, while wO and two 13C s contribute to (M + 2)+. The calculated intensities of (M + If- and (M + 2)+ relative to M+ (as 100) are tabulated in Table 9-5 for elemental composition of ions up to C20. The table applies to fragment ions as well as molecular ions, but the intensity data from fragment ions very often is complicated by overlapping peaks. 

Other measures of properties in 3D, such as Molecular Lipophilicity Potential (MLPot) and Molecular Hydrogen Bond Potential (MHBP), have been used to characterize 3D properties. They are defined for points on a molecular surface created around the molecule and calculated from the summation of contributions from the substructural fragments making up the molecule weighted by the distance function. The hydrogen bond potentials include an angle-dependent function. 

The work of Ertl et al. (2000) also demonstrates that it is not always necessary to use parameters from 3D analysis these can be substituted for more rapidly calculable parameters. In this paper the authors showed that the PSA of a molecule, calculated using the sum of fragment contributions available from tables, produced practically identical results when compared to calculating the surface from a geometry-optimised 3D structure. This means that sufficiently accurate PSA values can be incorporated into screens without requiring excessive computational time. 

Fig. 20.7. The upper panel shows the ion beam profiles of the C+ and H+ fragment ions in the z-direction, produced by electron impact ionization of methane and acetylene at an electron energy of 100 eV. The ion signal was measured as a function of the voltage on the z-deflector pair. In the lower diagram the initial kinetic energy distributions are displayed that were calculated from the z-profiles shown above. The initial kinetic energy distribution of both fragment ions consist of two parts designated as thin lines. The sum of the two contributions represents the total initial kinetic energy distribution and is displayed as a thick line in the same line style...

Substituent descriptors defined by measuring the additive contributions of molecular fragments to the hydrogen bonding ability of a molecule [Seiler, 1974]. Such descriptors are calculated from the difference in logP value in two solvent/water systems ... 

While these models have clear physical meaning and are easily interpretable, their disadvantage is the requirement to experimentally determine some descriptors. There are, however, possible solutions to this problem. Recently methods to calculate Abraham s descriptors directly from 2D molecular structure were proposed [40]. SPARC uses fragment contributions to predict solubility of new molecules. In this case, nevertheless, these methods can have the same problems as other fragmental methods. 

Palm et al. [3] took into account the flexibility of molecules by using molecular mechanics to calculate an averaged PSA according to a Boltzmann distribution. Later Clark [4,5] found that the use of a representative conformation was sufficient for the calculation of reliable PSA values. Ertl [6] developed a method to calculate PSA as the sum of fragment contributions and proposed a topological PSA (TPSA). The advantage of TPSA is that it can be directly calculated from the 2D chemical structure, which makes the calculation rapid and reproducible. 

Calculations employing the additivity of contributions from fragments are illustrated in Scheme 13 for the dissociation of the C(i, hydroxyl of glucose and a secondary amine. Tables of ApA, for fragments are given in Appendix 3 (Tables 9a and 9b) they may be used to calculate pA values by a simple additive protocol (the ApA method). 

The contribution of groups or fragments to the retention volume at different temperatures (Vai) can be calculated from the retention volumes of compounds at the same temperatures (Va) and then the contribution of groups to the heat of adsorption from equation ... 

Direct ES-MS characterization of a combinatorial library has been performed on the example of modified xanthene derivatives [30]. To circumvent the analysis of 104 to 10s possible compounds, small representative sublibraries rather than the whole library were synthesized and investigated [31].The results obtained were then extrapolated to the synthesis of the target library. A xanthene library was also used for ES-FT-ICR-MS investigation [32], A more recent contribution deals with the calculation of elemental compositions from FTICR mass spectra. FIowever,the mass accuracy required increases exponentially with the mass of the analyte [33], Therefore, elemental compositions are calculated from the exact measurement of fragment ions performing MS"-experiments [34],... 

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