Hansch approach to QSAR

The information contained in karma s knowledge bases is based upon quantitative structure-activity relationships (QSAR), kinetic data, and structural chemistry. The combination of QSAR and kinetic data allows for the study of enzyme-ligand interactions. The Hansch approach to QSAR, based on a set of congeners, states ... 

Many different approaches to QSAR have been developed since Hansch s seminal work. These include both two-dimensional (2D) and 3D QSAR methods. The major differences among these methods can be analyzed from two viewpoints (1) the strucmral parameters that are used to characterize molecular identities and (2) the mathematical procedure that is employed to obtain the quantitative relationship between a biological activity and the structural parameters. 

Historically, this is the most popular mathematical approach to QSAR. The major contribution of Hansch analysis is in recognizing the importance of logP, where P is the octanol-water partition coefficient. LogP is perhaps the most important measure of a... 

To design for selectivity, then, one should follow the relationship between selectivity and the difference in log P between two relevant solvent systems, and maximize this difference by choice of appropriate substitution. Young et al. (1988) have made use of A log P between octanol and cyclohexane systems to model successfully accumulation in brain tissue, giving support to this new, QSAR-based approach to selectivity enhancement. Related to this approach is the older and well-established principle that for keeping drugs away from the CNS, one should design them to have lipophilicity either much less than, or much greater than, a log P value of 2.0 in the octanokwater system (Hansch et al., 1987 see also Section 2.3.1). 

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. 

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 ... 

Hansch C (1969) A quantitative approach to biochemical structure-activity relationships. Acc Chem Res 2 232-239 Kubinyi H (2002) From narcosis to hyperspace The history of QSAR. Quant Struct Act Relat 21 348-356 Lemont KB, Lowell H (1999) Molecular Structure Description The Electrotopological State. Academic Press, San Diego, CA, USA... 

Based on the earlier work of Meyer and Overton, who showed that the narcotic effect of anesthetics was related to their oil/water partition coefficients, Hansch and his co-workers have demonstrated unequivocally the importance of hydrophobic parameters such as log P (where P is, usually, the octanol/water partition coefficient) in QSAR analysis.28 The so-called classical QSAR approach, pioneered by Hansch, involves stepwise multiple regression analysis (MRA) in the generation of activity correlations with structural descriptors, such as physicochemical parameters (log P, molar refractivity, etc.) or substituent constants such as ir, a, and Es (where these represent hydrophobic, electronic, and steric effects, respectively). The Hansch approach has been very successful in accurately predicting effects in many biological systems, some of which have been subsequently rationalized by inspection of the three-dimensional structures of receptor proteins.28 The use of log P (and its associated substituent parameter, tr) is very important in toxicity,29-32 as well as in other forms of bioactivity, because of the role of hydrophobicity in molecular transport across cell membranes and other biological barriers. 

C. Hansch, in QSAR Rational Approaches to the Design of Bioactive Compounds, C. Silipo and A. Vittoria, Eds., Elsevier, Amsterdam, 1991, pp. 3-10. New Perspectives in QSAR. 

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. 

Since the early work of Hansch et al., numerous examples of the quantitative correlation of biological activity with chemical structure have been reported. The success of QSAR relies heavily on the use of partition coefficients (log P or n) in extending the linear free-energy relationship (LEER) from homogenous organic chemical systems (i.e., the Hammett-Taft type approach) to compartmentalized heterogenous biological systems. 

Derived from physical organic chemistry and the - Hammett equation, this can be considered to be the first approach to modern QSAR studies. Proposed by Hansch and co-workers in the early 1960s [Hansch et al, 1962 Hansch et al, 1963 Hansch and Fujita, 1964 Hansch et al, 1965 Hansch and Anderson, 1967 Hansch, 1969 Hansch, 1971 Hansch, 1978], it is the investigation of the quantitative relationships between... 

Hansch, C. The physicochemical approach to drug design and discovery (QSAR). Drug Dev. Res. 1981, 1, 267—309. 

Hansch, C Gao, H. and Hoekman, D. (1998) A generalized approach to comparative QSAR, in Comparative QSAR (ed. J. Devillers), Taylor Francis, Washington, DC, pp. 285-368. 

Pre-Qsar" Series Development. Potency (Log 1/c) values for the first nineteen pyranenamlnes to be synthesized and tested In the PCA assay, prior to the use of QSAR In this series, appear In part A of Table I. The majority of these derivatives were synthesized in response to a newly proposed (at that time) decision model, the Topllss operation scheme or "tree .Q). Based on the observation that physlcochemlcally-based substituent constants are an aspect of the Hansch approach which is easier for synthetically oriented chemists to assimilate than is regression analysis, Topllss proposed specific sequences of substituted derivatives to be synthesized, with the next choice at each sequential step being governed by whether the preceding compound displayed either Increased, decreased, or unaltered potency. Retrospective studies... 

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