Structure-activity Free-Wilson approaches

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. 

Quantitative Structure-Activity Relationship (QSAR) approach was first developed by Cros (1863) and Brown and Fraser (1868). In the 1960s, C. Hansch, T. Fujita, S. M. Free Jr. and J. W. Wilson started what is now considered to be classical QSAR. A series of powerful advanced computer tools have now been introduced, increasing the capacity of QSAR. 

Kubinyi, H., Kehrhahn, . H. (1976) Quantitative structure-activity relationships. 1. The modified Free-Wilson approach. JMed Chem 19(5), 578-586. 

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

Besides the Hansch approach, other methodologies were also developed to tackle structure-activity questions. The Free-Wilson approach addresses structure-activity studies in a congeneric series as described in Equation 1.5(22). 

The Free-Wilson approach is truly a structure-activity-based methodology because it incorporates the contributions made by various structural fragments to the overall biological activity (22, 193, 194). It is represented by Equation 1.78. 

Kubinyi, H. and Kehrhahn, Q.M. (1976). Quantitative Structure-Activity Relationships. 1. The Modified Free-Wilson Approach. J.Med.Chem., 19, 578-586. 

Kubinyi H, Kehrhahn OH. Quantitative structure-activity relationships 1. The modified free-Wilson approach. J Med Chem 1976 19 578-86. 

Besides the Hansch apvproach, other methodologies were also developed to deal with structure- activity questions. The Free-Wilson approach (Free and Wilson, 1964) addresses structure-activity studies in a congeneric series in which the contribution of each structural feature was a parameter of interest. These parameters, also called indicator variables, codify the presence or absence of particular structural feature. They are assigned the binary values of 1 and 0, accordingly. 

Quantitative structure-activity relationships (QSAR) correlate the dependence of various biological activities on different physicochemical properties (Hansch analysis, extrathermo-dynamic approach) or on the presence and absence of certain structural features (Free-Wilson analysis). " In addition, the concept of Hansch analysis is used to correlate different biological activities, e.g., in vitro and in vivo, with each other. ... 

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. 

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. 

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. 

Structure/Response Correlations, Hansch analysis, Hammett equation, Free-Wilson analysis. Linear Solvation Energy Relationships, Linear Free Energy Relationships, group contribution methods, substituent descriptors, extrathermodynamic approach, and biological activity indices. 

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