Structure-activity relationships similarity principle

Whatever methods are employed to link assessment end points with measures of effect, it is important to apply the methods in a manner consistent with sound ecological and toxicological principles. For example, it is inappropriate to use structure-activity relationships to predict toxicity from chemical structure unless the chemical under consideration has a similar mode of toxic action to the reference chemicals. Similarly extrapolations from upland avian species to waterfowl may be more credible if factors such as differences in food preferences, physiology, and seasonal behavior (e.g., mating and migration habits) are considered. 

Once a lead is found, we have to focus in our search of property space as rapidly as possible to understand structure-activity relationships and perhaps build pharmacophore maps. To do this, we need to design more compounds to explore ranges of properties centered around our lead. This explosion of compounds is a knowledge-gathering process which, when the compounds are tested, should increase the understanding of bioactivity. By application of the neighborhood principle to eliminate similar molecules, any molecules selected for synthesis will likely have several hundred or a thousand similar structures that are stored in a virtual library. These often represent an ideal starting point for lead follow-up. 

Quantitative structure-activity relationships are primarily used for drug design. The underlying principle is that the shape and noncovalent interactions are the main contributors to the selectivity of the binding of substrates to an active center. Therefore, it must be possible to correlate structural properties of substrates with their activity. The assumptions on which QSAR methods are generally based are that all substrates bind to the same site, that structurally related compounds bind with a similar orientation and that dynamic effects can be ignored. 

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. 

As discussed in FDA s Preparation of Food Contact Notifications for Food Contact Substances Toxicology Recommendations (FDA, 2002), FDA has set forth minimum testing recommendations for tiered levels of expected consumer exposure. These recommendations are based on the general principle that the potential risk is likely to increase as exposure increases. In addition, submitters are encouraged to discuss the structural similarity of their food contact material or its constituents to known mutagens or carcinogens. This analysis is termed structure-activity relationship (SAR) analysis and is recommended for all exposures (discussed further below). Table 7.1 summarizes... 

The conceptual basis for similarity analysis is provided by the similarity-property principle that states that similar molecules have similar biological activity.This rather intuitive principle has been widely accepted and substantiated by a wealth of observations. The success of many similarity-based virtual screening calculations can only be rationalized on the basis of this principle. However, minor modifications in molecular structure can dramatically alter the biological activity of a small molecule. This situation is exploited in lead optimization elforts, but limits the potential of similarity methods. These considerations also suggest that there must be fundamental dilferences between the structure-activity relationships (SARs). Thus, difierent types of SARs are expected to critically determine the success of similarity methods and systematic SAR analysis helps to better understand on a case-by-case basis why similarity methods might succeed or fail. 

For illustration, we shall consider here one of the nonlinear variable selection methods that adopts a k-Nearest Neighbor (kNN) principle to QSAR [kNN-QSAR (49)]. Formally, this method implements the active analog principle that lies in the foundation of the modern medicinal chemistry. The kNN-QSAR method employs multiple topological (2D) or topographical (3D) descriptors of chemical structures and predicts biological activity of any compound as the average activity of k most similar molecules. This method can be used to analyze the structure-activity relationships (SAR) of a large number of compounds where a nonlinear SAR may predominate. 

CSPs [27], In biological systems, the TPI model was first successfully applied by Ogston to explain the enzymatic formation of ketoglutarate from achiral citrate and decarboxylation of L-serine to glycine by enzymes [28], Based on the same principle, Shallenberger et al. [29] established a similar model to explain how a sweet-taste receptor of the tongue distinguished D- and L-amino acids. In medicinal chemistry, the TPI model is a key element in structure-activity relationship studies [30],... 

In the context of compound partitioning, it should also be considered that relationships between structural and biological similarity can differ significantly. Much of the current molecular similarity research is based on the fundamental, and rather intuitive, similar property principle (18), which states that compounds with similar structures should generally have similar biologically activity. On the other hand, it is well known that minute structural modifications of active com-... 

---