Hansch-type analysis

The classical QSAR methodology started 1964 with the publications of Hansch and Fujita (1964) and Free and Wilson (1964) and the statement of Hansch (1969) resulted from a proposal by Fujita. They proposed to combine several physiochemical parameters (tt, a), also called descriptors, in a quantitative model. This Hansch-type analysis is very flexible and describes many different kinds of biological activities, e.g. in vitro data such as enzyme inhibition (Kubinyi 2002) ... 

It was also shown that the "ip index could be used as a significant second variable in the QSAR equation. Hansch-type analysis yielded r = 0.90. ... 

PLS was advantageous when studying the relationship of the toxicity of thiify triazines on Daphnia magna (25), and in a comparison between Hansch analysis and PLS analysis, using the same data set, it was shown that tiie multivariate approach of PLS provided more useful models than the Hansch type approach (26). 

Their values were chosen as a first approximation to represent the redox potentials of these three kinds of compounds in a Hansch-type multiple regression analysis study. 

The first approach mentioned was chosen in the C-QSAR database [34] using Hansch-type QSAR equations [35], Its advantage is that these models are easy to apply and interpret. However, each model has a limited applicability domain (Figure 12.1) thus only toxicity predictions for compounds belonging to these specific classes are suitable. Unfortunately, no analysis of the predictive power of a test set has been published to date. 

Still, whatever the computational procedure approached, either of that of Hansch type, 3D, decisional, or orthogonal ones, see the Section 2.5 of this Conclusion for detailed presentation, the problem of delivering the molecular interaction mechanism as a QSAR analysis result was... 

The Free-Wilson analysis provides more site-specific information than a Hansch analysis. It is recommended to carry out a Free-Wilson analysis first in order to obtain an idea of the importance of the substituent groups and of the sensitivity of the substitution sites. This type of analysis can be regarded as being qualitative, as it points to the important pharmacophores in the molecule. The information thus obtained may guide the selection of the appropriate physicochemical, topological... 

Substituent Parameters. A significant advance was made, in the structure-activity studies with the Hill reaction, when Hansch and Deutsch (12) evaluated some of the published Hill inhibition data with a multiple regression analysis, an extra-thermodynamic approach, or the so-called sigma, pi (a, T ) regression analysis. The principle of the approach rests on the assumption that changes in biological activity can be correlated with measurable molecular or substituent parameters. This analysis involved equations of the following type ... 

These efforts were guided by the study of quantitative structure-activity relationships (QSAR) following the Hansch approach. In this method linear free-energy related and other electronic, hydrophobic, and steric substituent constants are used for a quantitative analysis of the possible ways in which substituents may modulate bioactivity in a congeneric series. In the QSAR studies of benzoylphenyl ureas the electronic Hammett a-constants and the hydro-phobic Hansch n-constants were used. To measure the steric influences, steric substituent constants of a new type (B1,B2,B3,B4, and L) were applied which had recently been introduced by us and which give improved correlations in comparison with the steric Es constants used in the literature hitherto (21, 22). The constants B- toBj are measures of the widths of substituents in four rectangular directions. The L-constant accounts for the length of a substituent ... 

The epoch of QSAR (Quantitative Structure-Activity Relationships) studies began in 1963-1964 with two seminal approaches the a-p-7i analysis of Hansch and Fujita " and the Free-Wilson method. The former approach involves three types of descriptors related to electronic, steric and hydrophobic characteristics of substituents, whereas the latter considers the substituents themselves as descriptors. Both approaches are confined to strictly congeneric series of compounds. The Free Wilson method additionally requires all types of substituents to be suflficiently present in the training set. A combination of these two approaches has led to QSAR models involving indicator variables, which indicate the presence of some structural fragments in molecules. 

On the basis of the origin of molecular descriptors used in calculations, QSAR methods can be divided into three groups. One group is based on a relatively small number (usually many times smaller than the number of compounds in a data set) of physicochemical properties and parameters describing,for example, hydrophobic, steric, and electrostatic effects. Usually, these descriptors are used as independent variables in multiple regression approaches (18) Jn the literature, these methods are typically referred to as Hansch analysis (8).These types of descriptors and corresponding linear optimization methods used in traditional QSAR analyses are discussed extensively in the chapter by Celassie (7) and therefore is not reviewed here. 

I had a question the other day, You know what I d like to do, I d like to see a Hansch analysis on a series of compounds and then I d like to see some molecular orbital calculations on the same series. The point is that you don t compare this type of correlation with that type of correlation in this sense. Rather I think it is more important to look at a particular model and then use whatever techniques you need to get the parameters that go into that model, whether you measure the dipole moment or whether you calculate it from wavefunctions or whether you take the charge densities from pK measurements or whether you calculate the charge density. It is not the Hansch model vs. molecular orbitals. That makes no sense to me. Rather it is using molecular orbital calculations to get at fundamental properties of the molecules—the same way that you would get at them if you measured the infrared absorption of... 

Fujita Ban-type indicator variables can be combined with Hansch analysis to a mixed approach (see chapters 3.8 and 4.3) [22, 390, 391]. 

The use of Free Wilson-type indicator variables in Hansch analysis has been discussed in chapters 3.8, 4.3, and 7 [21, 390, 391, 393]. Nonadditivities in Free Wilson analyses due to nonlinear lipophilicity-activity relationships have been discussed in chapter 4.3 [22, 390—392, 394]. 

We have successfully applied LOGANA and LOGON in a number of cases [122-126, 171] and use both methods routinely. As a simple example we shall present here results [122] obtained for a series of fungicidal carboxamides as inhibitors of succinate dehydrogenase (experimental data from [172]). The series comprises 89 compounds of the general stractuie presented in Fig. 5. Stmctuial variations are so extensive that QSAR methods of the Hansch or Free-Wilson type do not lead to meaningful results. Tables 6 and 7 summarize the topological descriptors used in the analysis. 

The study of structure-reactivity relationships by the organic chemist Hammett showed that there is often a quantitative relationship between the two-dimensional structure of organic molecules and their chemical reactivity. Specifically, he correlated the changes in chemical properties of a molecule that result from a small change in its chemical structure that is, the quantitative linear relationship between electron density at a certain part of a molecule and its tendency to undergo reactions of various types at that site. For example, there is a linear relationship between the effea of remote substituents on the equilibrium constant for the ionization of an acid with the effect of these substituents on the rate or equilibrium constant for many other types of chemical reaction. The relative value of Hammett substituent constants describes the similarity of molecules in terms of electronic properties. Taft expanded the method to include the steric hindrance of access of reagents to the reaction site by nearby substituents, a quantitation of three-dimensional similarity. In addition, Charton, Verloop, Austel, and others extended and refined these ideas. Finally, Hansch and Fujita showed that biological activity frequently is also quantitatively correlated with the hydrophobic character of the substituents. They coined the term QSAR, Quantitative Structure-Activity Relationships, for this type of analysis. 

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