Other steric parameters

Charton [61] has postulated a steric scale (Eqn. 75) which is the difference between the Van der Waal s radius for a symmetrical substituent and hydrogen 

The values for primary (symmetrical) substituents were extended to unsymmet- 

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Two other steric parameters are independent of any kinetic data. Charton s v values are derived from van der Waals radii/ and Meyer s values from the volume of the portion of the substituent that is within 0.3 nm of the reaction center. The V values are obtained by molecular mechanics calculations based on the structure of the molecule. Table 9.7 gives v and value.s for some groups. As can be seen in the table, there is a fair, but not perfect, correlation among the Ei, v, and values. Other sets of steric values, (e.g., and have also been proposed. ... 

Table 2.4-2. Correlation of Tolman s steric parameter with other steric parameters, using the isosteric principle 74, 7S) ...

Irrmost correlations in this review, the steric parameters are supposed to be best among others. In deriving Eq. 43 for N-phenyl tetrahydrophthalimide herbicides, STERIMOL parameters are the best ones 42). In Eq. 53 for lindane analogs, Vw works much better than MR 70). However, this does not necessarily mean that the correlations mentioned here are always finalized. Further improvement may be possible using other steric parameters. 

While the development of the Taft parameter is similar to that of Hammett and Hansch, / )-val ucs are based on rate constants instead of equilibrium constants. The Taft parameter is a measure of changes in activation energy, not standard free energy. Of the Hammett, Hansch, and Taft parameters, the Taft parameter is utilized the least in QSAR studies. Other steric parameters have been developed over time, and like the Taft parameter, all have shortcomings. One alternative steric parameter was developed by Marvin Charton of Pratt Institute in New York. Charton s parameter is based on the van der Waal radius of a substituent.6 Another alternative steric model is the STERIMOL parameter set developed by Arie Verloop of Philips-Duphar in Holland.7 Unlike Taft and Charton, Verloop... 

The work described here consists of two types of approaches to the steric fit problem, The first approach consists of developing new parameters to describe different characteristics of the molecular shape Ci.e, branching, bulkiness) this is done by means of topological indices. The second approach is based on minimal steric differences, a measure for steric misfit which depends not only on molecular shape,but also on the receptor and allows a guess of the shape of the receptor cavity. Brief reviews will be given on other steric parameters which will often be compared, in QSAR s, with parameters developed by the authors of these Lecture Notes, Electronic parameters and hydrophobi-city-intermolecular force parameters, to be used together with steric parameters in OSAR s, are also briefly discussed. Other items include the metric introduced by minimal steric difference and computer programs developed in connection with our steric parameters. 

The B -B, L parameters have at least two important advantages in comparison to other steric parameters (i) they describe more adequately nonsymmetrical substituents and emphasize the directional (vectorial) character of steric effects, extending thus the possibilities of OSAR analysis, (ii) they offer more detailed information about the actual conformation of the receptor when it is attacked by the effector. Nevertheless, the fact that it introduces at once five predictor variables in the regressional analysis requires relatively large series of data in order to obtain reliable results. 

A Brief Review of the QSAR Technique. Most of the 2D QSAR methods employ graph theoretic indices to characterize molecular structures, which have been extensively studied by Radic, Kier, and Hall [see 23]. Although these structural indices represent different aspects of the molecular structures, their physicochemical meaning is unclear. The successful applications of these topological indices combined with MLR analysis have been summarized recently. Similarly, the ADAPT system employs topological indices as well as other structural parameters (e.g., steric and quantum mechanical parameters) coupled with MLR method for QSAR analysis [24]. It has been extensively applied to QSAR/QSPR studies in analytical chemistry, toxicity analysis, and other biological activity prediction. On the other hand, parameters derived from various experiments through chemometric methods have also been used in the study of peptide QSAR, where partial least-squares (PLS) analysis has been employed [25]. 

The importance of lipophilicity to bitterness has been well established, both directly and indirectly. The importance of partitioning effects in bitterness perception has been stressed by Rubin and coworkers, and Gardner demonstrated that the threshold concentration of bitter amino acids and peptides correlates very well with molecular connectivity (which is generally regarded as a steric parameter, but is correlated with the octanol-water partition coefficient ). Studies on the surface pressure in monolayers of lipids from bovine, circumvallate papillae also indicated that there is a very good correlation between the concentration of a bitter compound that is necessary in order to give an increase in the surface pressure with the taste threshold in humans. These results and the observations of others suggested that the ability of bitter compounds to penetrate cell membranes is an important factor in bitterness perception. 

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

Simple branching equation (SB) A topological method for describing steric effects which takes into account the order of branching by using as parameters n , the number of atoms other than H that are bonded to the i -th atoms of the substituent, w The number of branches on the f -th atoms of a substituent. These are the steric parameters used in the SB equation. 

To verify such a steric effect a quantitative structure-property relationship study (QSPR) on a series of distinct solute-selector pairs, namely various DNB-amino acid/quinine carbamate CSPpairs with different carbamate residues (Rso) and distinct amino acid residues (Rsa), has been set up [59], To provide a quantitative measure of the effect of the steric bulkiness on the separation factors within this solute-selector series, a-values were correlated by multiple linear and nonlinear regression analysis with the Taft s steric parameter Es that represents a quantitative estimation of the steric bulkiness of a substituent (Note s,sa indicates the independent variable describing the bulkiness of the amino acid residue and i s.so that of the carbamate residue). For example, the steric bulkiness increases in the order methyl < ethyl < n-propyl < n-butyl < i-propyl < cyclohexyl < -butyl < iec.-butyl < t-butyl < 1-adamantyl < phenyl < trityl and simultaneously, the s drops from -1.24 to -6.03. In other words, the smaller the Es, the more bulky is the substituent. The obtained QSPR equation reads as follows ... 

The results of the studies will be summarized. Details of the QSAR analyses are or will be published elsewhere, including intercorrelation matrices of the steric parameters mentioned. But relevant conclusions from e.g. intercorrelations will be dicussed. At this moment the STERIMOL method has been applied successfully in about 50 publications often with better results than other steric approaches, including MTD and MTD, especially in series with few substituent positions. A recent example is our study of DDT analogs. Brown et al. (9J analysed a series of 21 derivatives using the van de Waals (Vw) volumes as steric parameters. In Table I the equations are given in which the steric parameters are compared. 

Similar dependence of the ZFS parameters on the rigidity of matrices is observed for many other sterically congested triplet carbenes and hence can be considered as an indication of such steric strain. ... 

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