Free-Wilson

The work by Hammett and Taft in the 1950s had been dedicated to the separation and quantification of steric and electronic influences on chemical reactivity. Building on this, from 1964 onwards Hansch started to quantify the steric, electrostatic, and hydrophobic effects and their influences on a variety of properties, not least on the biological activity of drugs. In 1964, the Free-Wilson analysis was introduced to relate biological activity to the presence or absence of certain substructures in a molecule. 

Free-Wilson method Freeze concentration Freeze drying... 

The second extrathermodynamic method that we discuss here differs from Hansch analysis by the fact that it does not involve experimentally derived substitution constants (such as o, log P, MR, etc.). The method was originally developed by Free and Wilson [29] and has been simplified by Fujita and Ban [30]. The subject has been extensively reviewed by Martin [7] and by Kubinyi [8]. The method is also called the de novo approach, as it is derived from first principles rather than from empirical observations. The underlying idea of Free-Wilson analysis is that a particular substituent group at a specific substitution site on the molecule contributes a fixed amount to the biological activity (log 1/C). This can be formulated in the form of the linear relationship ... 

Table 37.3 shows the complete table of eight indicator variables for 10 triply substituted tetracyclines [31 ] that have been tested for bacteriostatic activity (1/Z), which is defined here as the ratio of the number of colonies grown with a substituted and with the unsubstituted tetracycline. In this application we have three substitution positions, labelled U, V and W. The number of substituents at the three sites equals 2,3 and 3, respectively. Arbitrarily, we chose the compound with substituents H, NOj and NO2 at the sites U, V and W as the reference compound. This leads to a reduction of the number of indicator variables from eight to five, as shown in Table 37.4. The solution of the Free-Wilson model can be obtained directly by means of multiple regression ...

In a broad sense, one may include the Free-Wilson equation within the class of linear free energy relationships (LFER). It is also subjected to the assumption of additivity of the contributions to the biological activity by substituent groups at different substitution sites. The assumption requires, for example, that there is no hydrogen bonding interaction between the various substitution groups. 

The interpretation of the result of a Free-Wilson analysis is somewhat different from that of a Hansch analysis. The coefficients in the Hansch model represent absolute contributions to the biological activity of a compound from the various... 

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... 

Principal components analysis can also be used in the case when the compounds are characterized by multiple activities instead of a single one, as required by the Hansch or Free-Wilson models. This leads to the multivariate bioassay analysis which has been developed by Mager [9]. By way of illustration we consider the physicochemical and biological data reported by Schmutz [41] on six oxazepines... 

P.N. Craig, Comparison of the Hansch and Free-Wilson approaches to structure-activity correlation, In Biological Correlations — The Hansch Approach (R.F. Gould, Ed.). Advances in Chemistry Series, No. 114. American Chemical Society, Washington DC, 1972, pp. 115-129. P.N. Craig, Interdependence between physical parameters and selection of substituent groups for correlation studies. J. Med. Chem., 14 (1971) 680-684. 

Zf Method This method developed by Rekker and Mannhold [36] uses fragmental hydrophobicity coefficients and correction factors obtained via a reductionist approach, deriving the constants for each fragment from Free-Wilson type... 

For activity of ACTH-derived peptides at the receptor for pole-jumping activity, the basic requirement seems to be the presence of a Phe and Met residue in close proximity. It is interesting to see that Phe and Met are close together in an a-helical structure in ACTH peptides (and as intra-chain neighbours in Met-enkephalin) and in the crystalline state in ACTH-(4-10) as a 3-pleated sheet and in ACTH-(4-7) in the form of a horseshoe this close proximity is in line with the results of a Free-Wilson type of analysis. 

Nevertheless, Hansch analysis revolutionized drug molecule optimization and directly led to two other strategies for molecule optimization the Free-Wilson method and the Topliss decision tree. 

The Free-Wilson Method. This method also assumes that biological activity can be described by the additive properties of the substituents on a basic molecular structure. In the Fujita-Ban modification of this method... 

Topliss Decision Tree Method. This method is quicker and easier to use than the Hansch method. The Topliss scheme is an empirical method in which each compound is tested before an analog is planned, and is compared in terms of its physical properties with analogs already planned. Like the Free-Wilson method, the Topliss decision tree is no longer extensively used. The 2D- and 3D-QSAR methods are gradually supplanting the ID methods. 

Application of Free-Wilson Selectivity Analysis for Combinatorial Library Design... 

Key words QSAR, Free-Wilson, MLR, virtual libraries, combinatorial chemistry, protein kinase,... 

In the chapter, we report a successful application of the Free-Wilson (26-30) methodology to model structure-activity/selectivity relationships. The Fujita-Ban (31-34) modification of Free-Wilson coupled with multiple linear regression... 

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