Hansch/Free-Wilson

A large combined data set of 48 propafenones was then analyzed by both Free-Wilson analysis and a combined Hansch/Free-Wilson approach using an artificial neural network (ANN). With this approach it was possible, in contrast to conventional MLR analysis, to correctly predict the MDR-reversing activity of 34 compounds of the data set after the ANN was trained by only 14 compounds. Best results were obtained using those descriptors showing the highest statistical significance in MLR analysis [150]. 

Hansch-Free-Wilson mixed models - Hansch analysis... 

Duperray, B., Chastrette, M., Makabeth, M.C. and Pacheco, H. (1976a). Analyse Comparative de Correlations Hansch, Free-Wilson et Darc-Pelco pour une Famille de Bactericides des Phenols Halog6n6s. EurJ.Med.Chem., 11,323-336. 

Hall, L.H. and Kier, L.B. (1978a). A Comparative Analysis of Molecular Connectivity, Hansch, Free-Wilson and Darc-Pelco Methods in the SAR of Halogenated Phenols. Eur.J.MedChem.,... 

Tmej C, Chiba P, Huber M, Richter E, Hitzler M, Schaper KJ, Ecker G. A combined Hansch/free-Wilson approach as predictive tool in QSAR studies on propafenone-type modulators of multidrug resistance. Arch Pharm (Weinheim) 1998 331 233 10. 

Hansch-Free-Wilson mixed models were also proposed [Kubinyi, 1976a] by combining the two approaches in a single model. A quadratic term accounting for hydrophobic interactions (usually log P or n Hansch-Fujita constant) can be added to the Free-Wilson (or Fujita-Ban) model as... 

Hansch bilinear models —> Hansch analysis Hansch descriptors —> Hansch analysis Hansch-Free-Wilson mixed models Hansch analysis... 

Equations (9) and (10) constitute the fundament of all QSAR studies. Since 1964, they have remained essentially unchanged, with the exception of two minor modifications. Improvements resulted from the combination of Hansch equations with indicator variables [22], which may be considered as a mixed Hansch/Free-Wilson model (Eq. (11)) [23], and from the formulation of a theoretically derived nonlinear model for transport and distribution of drugs in a biological system, the bilinear model (Sec. 4 Eq. (30)) [24] ... 

The DARC-PELCO approach [418—423] is a simple application of a hyperstructure concept to the Free Wilson method while the approach may be appropriate for extremely large data sets, e.g. for the derivation of lipophilicity contributions from partition coefficients, it is usdess for most structure-activity analyses, due to the much too large number of variables (compare eqs. 199 and 200, chapter 8) [390, 391]. The results from Hansch, Free Wilson, and DARC-PELCO analyses have been compared with each other [421, 422, 424] no advantages of the latter approach could be seen. 

Pharm. Med. Chem., 331, 233 (1998). A Combined Hansch/free Wilson Approach as Predictive Tool in QSAR Studies on Propafenone-Type Modulators of Multidrug Resistance. 

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. 

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 ... 

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. 

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. 

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. 

Schaad, L. J., Hess, B. A., Purcell, W. P., Cammarata, A., Franke, R., Kubinyi, H. (1981) Compatibility of the Free-Wilson and Hansch quantitative structure-activity relations. JMed Chem 24(7), 900-901. 

The Free-Wilson method of deriving quantitative structure-activity-relationships 101 uses implicit representations of physico-chemical properties and there are also numerous examples where indicator variables have been successfully included in the Hansch approach. 

Several SARs and QSARs have been derived from data on antineoplastic activity as well as for MDR-reversing activity. The Hansch approach, Free-Wilson, and neural network analysis have been applied. The importance of lipophilicity, molar refractiv-ity (MR), and charge for the description of activity is common to all derived relations. 

The statistical methods of QSAR modelling are based on the correlation of changes in biological/toxicological activity (AO) resulting from certain chemical modifications (AC), either directly by structural parameters, called Free Wilson-type relationships, or by the corresponding changes of molecular properties, called Hansch-type analyses (Kubinyi 2002) ... 

On the other hand, Free Wilson analysis is much more restricted than Hansch analysis, because of its many parameters and the corresponding decrease on the number of degrees of freedom of the statistical analysis (Kubinyi 2002). 

The Hansch-Fujita method, the Free-Wilson theory (described by Craig in Chapter 8), and the molecular orbital theory (described by Kier, Chapter 15) have greatly increased our understanding of the mode of action of many biological chemicals. It has also improved our ability to predict the activity of a variety of chemicals against plant and insect pests and certain pathogenic organisms. 

Comparison of the Hansch and Free-Wilson Approaches to Structure-Activity Correlation... 

The basic principles on which the Hansch multiple parameter method for structure-activity correlation depends are described. These are compared with the basic features of the Free-Wilson method for assigning additivity constants to structural features of related compounds. An example is given for which the two methods of analysis have led to similar structure-activity relationships. Factors which determine the particular method to use in a new situation are discussed. The Free-Wilson method is presented in considerable operational detail with special emphasis on the detection and avoidance of situations which lead to singularity problems in solution of the matrix. Favorable analyses, which result in additivity constants that can be correlated with known physical constants, may lead to predictions for new compounds not covered in the original matrix. 

Tihe two methods of structure-activity correlation which have received the most application in the past decade are the Hansch multiple parameter method, or the so-called extrathermodynamic approach, and the Free-Wilson, or additive model. The basic differences and similarities of these methods are discussed in this presentation. 

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