Quantitative structure-activity relationships refinement

An integrated testing strategy is any approach to the evaluation of toxicity which serves to reduce, refine or replace an existing animal procedure, and which is based on the use of two or more of the following physicochemical, in vitro, human (e.g., epidemiological, clinical case reports), and animal data (where unavoidable), and computational methods, such as (quantitative) structure-activity relationships ([Q]SAR) and biokinetic models. 

Diflubenzuron and its analogues aroused the interest of researchers engaged in quantitative structure-activity relationship (QSAR) studies. Thus, Verloop and Tipker (1977 1978) demonstrated on a number of diflubenzuron analogues the feasibility of STERIMOL parameters in QSAR analyses, permitting a refined insight into the shape of the substituents. Bordas et al. (1979) carried out a retrospective study of activity data on diflubenzuron derivatives, by using Free-Wilson analysis, factor analysis and principal component analysis. The factors extracted by principal component analysis and factor analysis were used as... 

Interestingly, most quantitative structural activity relationship (QSAR) studies usually commence by considering o (Hammett substitution constant) and, in case there exists more than one substituent, the a values are represented in a summed up manner as Za. Keeping in view the enormous quantum of synthetic newer target drug molecules, it has now become almost necessary and possible either to modify/refine or fine tune-up the QSAR equation. In fact, a substituent s resonance effect (R) and inductive effect (F) may be quantified as far as possible with the help of available tables of constants . In certain instances one may evidently observe that ... 

Chemical structure modifications which enhance activity and refine specificity will be followed up using medicinal chemistry methods, relating structures of compounds to activity in certain assays. These exercises will result in the definition of a quantitative structure activity relationship (SAR) for the series of compounds active in the assays. 

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. 

This section covers ab initio and density functional theory (DFT), semi-empirical and empirical, and molecular mechanics and molecular dynamics methods. For gas-phase structure determinations, a refinement to the use of ab initio calculations the SARACEN (Structure Analysis Restrained by Ab initio Calculations for Electron diffractioN) method, and other relevant theoretical and computational chemistry techniques, including quantitative structure-activity/property relationship (QSAR/QSPR) models for prediction of biological activity and physicochemical properties, are also covered. 

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