Reference molecule

Figure 2 40. To illustrate the isomorphism problem, phenylalanine is simplified to a core without representing the substituents. Then every core atom is numbered arbitrarily (first line). On this basis, the substituents of the molecule can be permuted without changing the constitution (second line). Each permutation can be represented through a permutation group (third line). Thus the first line of the mapping characterizes the numbering of the atoms before changing the numbering, and the second line characterizes the numbering afterwards. In the initial structure (/) the two lines are identical. Then, for example, the substituent number 6 takes the place of substituent number 4 in the second permutation (P2), when compared with the reference molecule.

In the example, we proceed from the right (rotated molecule) to the left (reference molecule). The first transposition is done with ligands 4 and 2, in order to obtain the fir.st part of the reference. scqttencc 1 2". Then, only a pcrmtttation of ligands 3 and 4 has to be done to obtain the reference matrix on the left-hand side. Thus, in total, we have executed two transpositions (4 2) and (3 4),... 

In the Fischer convention, the ermfigurations of other molecules are described by the descriptors d and L, which are assigned comparison with the reference molecule glyceraldehyde. In ertqrloying the Fischer convention, it is convenient to use projection formulas. These are planar representations defined in such a w as to convey three-dimensional structural information. The molecule is oriented with the major carbon chain aligned vertically in such a marmer that the most oxidized terminal carbon is at the top. The vertical bonds at each carbon are directed back, away fiom the viewer, and the horizontal bonds are directed toward the viewer. The D and L forms of glyceraldehyde are shown below with the equivalent Fischer projection formulas. 

At the present time, use of the Fischer convention is almost entirely restricted to carbohydrates, amino acids, and biologically important molecules of closed related structural types. The problem with more general use is that there are no adequate rules for deciding whether a diiral atom is like D-glyceraldehyde or L-glyceraldehyde when the structures are not closely similar to the reference molecules. This relationship is clear for carbohydrates and amino acids. 

Unfortunately, assignment of molecules that are not closely related to the reference molecules becomes a subjective matter of assigning which substituents are similar. The application of the terminology to cases in which the chiral centers are not adjacent is also ambiguous. As a result, the threo-erythro terminology is not a general method of specifying stereochemical relationships. 

To obtain the predicted shift for the carbon atom in methane, we subtract its absolute value from that of the reference molecule, resulting in a predicted shift of -3.9 ppm, which is in reasonable agreement with the experimental value of -7.0. Note the sign convention for shifts a negative number indicates that there is more shielding in the specified molecule than in the reference molecule, and a positive number indicates that there is less shielding than in the reference molecule. 

If / > 1 the structural change of the reference molecule affords a more lipophilic substance. / < 1 indicates that the hydrophilic character of the reference... 

The semiempirical methods represent a real alternative for this research. Aside from the limitation to the treatment of only special groups of electrons (e.g. n- or valence electrons), the neglect of numerous integrals above all leads to a drastic reduction of computer time in comparison with ab initio calculations. In an attempt to compensate for the inaccuracies by the neglects, parametrization of the methods is used. Meaning that values of special integrals are estimated or calibrated semiempirically with the help of experimental results. The usefulness of a set of parameters can be estimated by the theoretical reproduction of special properties of reference molecules obtained experimentally. Each of the numerous semiempirical methods has its own set of parameters because there is not an universial set to calculate all properties of molecules with exact precision. The parametrization of a method is always conformed to a special problem. This explains the multiplicity of semiempirical methods. 

This method estimates pA a values for oxygen acids from that of the reference molecule water (corrected for the number of acidic hydrogens) using terms... 

The same technique can be used in some cases to obtain accurate estimates of binding free energy differences for a set of ligands of interest [25, 31-34]. The molecule taken as the reference need not be a real molecule. Indeed, the reference molecule could be intermediate between a large set of molecules of interest, so that conformations that are sufficiently representative of them all are sampled in the reference simulation. The justification for this approach is discussed in detail in Chap. 6. To achieve this for a variety of substituted phenols, Liu et al. [25] added dummy atoms to the ring at the sites they wished to substitute. Such dummy atoms can be softer ... 

Here, rtJ is the distance between a softened atom i on the reference molecule and another atom j etJ and are the van der Waals interaction parameters for this pair,... 

When comparing different experimental sources of Caco-2 permeability data, quantitative comparison is almost impossible, due to intervariations of experimental procedures between laboratories, although standard protocols and reference molecules are often used. 

Scheme 11.16 Monitoring the relative reactivity values of four reference molecules.

Table 8.2 Mean absolute deviations (kcal/mol) for first-row reference molecules.8...

Our primary validation set for first-row compounds is derived from the original MNDO development [13, 41], but has been updated to include new experimental data for the reference molecules. Table 8.2 shows... 

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