Activity cliffs

Effective structure-activity relationship (SAR) generation is at the centre of any medicinal chemistry campaign. Much work has been done to devise effective methods to explain and explore SAR data for medicinal chemistry teams to drive the design cycles within drug discovery projects (1). Recent work on SAR generation highlights the commonly observed discontinuity of SAR and bioactivity data, the so-called activity cliffs (2). This also emphasises the need to empirically determine SAR for each lead... 

Maggiora, G. M. (2006) On outliers and activity cliffs - why QSAR often disappoints. 

Activity cliff, Structure-activity similarity maps, Structure-activity landscape index, Structure-activity... 

Structure-activity similarity (SAS) maps, first described by Shanmugasundaram and Maggiora (35), are pairwise plots of the structure similarity against the activity similarity. The resultant plot can be divided into four quadrants, allowing one to identify molecules characteristic of one of four possible behaviors smooth regions of the SAR space (rough), activity cliffs, nondescript (i.e., low structural similarity and low activity similarity), and scaffold hops (low structural similarity but high activity similarity). Recently, SAS maps have been extended to take into account multiple descriptor representations (two and three dimensions) (36, 37). In addition to SAS maps, other pairwise metrics to characterize and visualize SAR landscapes have been developed such as the structure-activity landscape index (SALI) (38) and the structure-activity index (SARI) (39). 

NSG that connect regions of low and high SAR discontinuity). Such SAR pathways represent a set of compounds that when ordered appropriately exhibit a continuous series of SAR changes. While network-based analyses of landscapes have seen much activity, an alternative visualization approach described by Seebeck et al. (42) abstracted the idea of the SALI metric and extended it to include the receptor. Using this technique they were able to highlight specific regions within protein-binding sites that are most likely to lead to activity cliffs. 

The concept of activity cliffs and the landscape paradigm have also been applied to R-groups, where an R-cliff occurs when a pair of compounds differs in a single R-group. This is clearly a specialization of the activity cliff concept, placing this type of analysis in the context of analogue series derived via R-group decompositions (43, 44). 

Medina-Franco JL, Martinez-Mayorga K, Bender A et al (2009) Characterization of activity landscapes using 2D and 3D similarity methods consensus activity cliffs. J Chem Inf Model 49(2) 477-491... 

Guha R, Van Drie JH (2008) The structure-activity landscape index identifying and quantifying activity-cliffs. J Chem Inf Model 48(3) 646-658... 

Seebeck B, Wagener M, Rarey M (2011) From activity cliffs to target-specific scoring models and pharmacophore hypotheses. ChemMed Chem 6(9)4630-1639... 

Sisay MT, Peltason L, Bajorath J (2009) Structural interpretation of activity cliffs revealed by systematic analysis of structure-activity relationships in analog series. J Chem Inf Model 49(10) 2179-2189... 

Figure 4.3 Example of an activity cliff illustrated by closely related adenosine deaminase inhibitors having dramatic potency differences. The introduction of a hydroxyl group that coordinates a zinc cation in the active site of the enzyme adds several orders of magnitude to the potency of an inhibitor.

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... 

The similarity threshold for ligand pairs that are considered in calculating the discontinuity score is set to 0.6. This relatively soft threshold value ensures that also potency differences between remotely similar compounds are taken into account and thus enables a thorough assessment of putative activity cliffs, which is further emphasized by multiplication by pair-wise ligand similarity. 

Failure of the congenericity principle has been recognized as one of the major problems for producing reliable QSAR models, unless the presence of the so-called activity cliffs is accounted for. The activity cliff was defined as the ratio of the difference in activity of two compounds to their distance in a given chemical space [Maggiora, 2006]. Activity cliffs arise when very similar compounds, whose similarity is measured by the set of molecular descriptors used to define the chemical space, possess very different activities. The presence of activity difFs leads to some important implications for QSAR modeling ... 

A quantification of the concept of presence of activity cliffs was proposed in terms of the SAL Index (or Structure-Activity Landscape Index), which for a pair of compounds is defined as [Maggiora, 2006 Guha and Ven Drie, 2008]... 

Another index for evaluating presence of activity cliffs is the SAR Index (or Structure-Activity Relationship Index), defined as a function of two separately calculated scores that assess intraclass diversity and activity differences of similar compounds [Peltason and Bajorath, 2007] ... 

The discontinuity score determines the average activity difference for pairs of similar compounds, which reveals the presence of activity cliffs as a major determinant of discontinuous SARs. To generate the discontinuity score, the following quantity is defined ... 

---