Analyzing the Nature of Structure-Activity Relationships

Similarity search calculations are known to show highly varying performance on dilferent compound activity classes. Methods of dilferent design and complexity 

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. 

In systematic SAR analysis, molecular structure and similarity need to be represented and related to each other in a measurable form. Just like any molecular similarity approach, SAR analysis critically depends on molecular representations and the way similarity is measured. The nature of the chemical space representation determines the positions of the molecules in space and thus ultimately the shape of the activity landscape. Hence, SARs may differ considerably when changing chemical space and molecular representations. In this context, it becomes clear that one must discriminate between SAR features that reflect the fundamental nature of the underlying molecular structures as opposed to SAR features that are merely an artifact of the chosen chemical space representation. Consequently, activity cliffs can be viewed as either fundamental or descriptor- and metrics-dependent. The latter occur as a consequence of an inappropriate molecular representation or similarity metrics and can be smoothed out by choosing a more suitable representation, e.g., by considering activity-relevant physicochemical properties. By contrast, activity cliffs fundamental to the underlying SARs cannot be circumvented by changing the reference space. In this situation, molecules that should be recognized as 

A set of inhibitors of the coagulation factor Xa is found to present prototypic continuous SARs. There is detectable correlation between 2D and 3D molecular similarity and most similar 2D structures bind very similarly and with 

A different example is provided by a set of elastase inhibitors. These ligands are also related by continuous SARs. This is reflected by the presence of highly potent inhibitors with diverse structures and, in addition, structurally similar ligands that display only minor potency differences. However, in contrast to factor Xa, 3D analysis reveals a more complex picture. Specifically, elastase accepts multiple binding modes, each of which is adopted by structurally 

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