Discontinuous SARs

Hence, the SAR Index yields values between 0 and 1. Low SARI values indicate discontinuous SARs, high SARI values continuous ones, and intermediate values heterogeneous SARs that combine continuous and discontinuous elements. 

Discontinuous SARs. Consistent with the results of our qualitative SAR analysis presented above, SARI scoring indicates that ribonuclease A inhibitors are a prototypic example of discontinuous SARs. The potency among these highly similar nucleotide analogs differs by up to three orders of magnitude (Figure 4.7b). As already mentioned above, these features clearly indicate the presence of discontinuous SARs. The low SARI score of 0.16 mirrors these findings. It results from the combination of a very low continuity score of nearly zero (0.004) that reflects the lack of structural diversity within the... 

Figure 4.10 Example of a heterogeneous SAR. Four inhibitors of vascular endothelial growth factor receptor (YEGFR-2) tyrosine kinase are shown. The two inhibitors at the top have different core structures but equally high potency and are thus part of a continuous SAR. By contrast, closely related analogs of each inhibitor shown at the bottom have several orders of magnitude lower potency, which is a characteristic feature of discontinuous SARs.

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 ... 

Figure 11.2 Heterogeneous SAR combining continuous and discontinuous SAR. Four cathepsin S inhibitors dispiay different SAR behavior, inhibitors reiated by a continuous SAR have comparabie potency vaiues despite structurai variations (top). In the...

For further characterization of activity landscapes, numerical SAR analysis functions were also proposed [47, 82]. Those functions globally characterize continuous and discontinuous SAR regions. 

While not exactly the same as the methods described above in that DOE cannot be applied retrospectively to diverse datasets, it has been used very successfully to guide the selection and evaluation of compounds from combinatorial libraries (59,60). However, DOE has been successfully applied only in cases where limited libraries of related compounds (e.g., peptides) were being evaluated. The reason for this is intuitively obvious, as one of the assumptions of DOE is that variability in the descriptors is continuous and related to activity over a smooth response surface, so that trends and patterns can be readily identified. With HTS data both of these assumptions are generally not true, as molecules can display discontinuous responses to changing features, and the SAR of even related compounds does not map to a smooth continuous response surface (for example, Fig. 2). 

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... 

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. 

SAR Index. The SAR Index (SARI) has recently been introduced to quantitatively capture the continuous, discontinuous, or heterogeneous nature of activity landscapes and SARs. Similar to SAS maps, it exclusively relies on the 2D structural similarity and potency distribution within a set of active compounds. However, SARI aims to categorize the SARs of a population of compound sets without employing idealized reference states. It generates a numerical index between 0 and 1 that reflects the (dis-)continuity of the SARs under consideration. SARI distinguishes between three major categories of... 

SARs continuous, discontinuous and heterogeneous. In the following, the conceptual framework of SARI will be presented and compound classes representative for the distinct SAR types are discussed. 

The SAR Index is ultimately calculated as the mean of the final scores. High continuity and discontinuity scores are indicative of opposite SAR characteristics and, therefore, the discontinuity score is subtracted from 1 to obtain a complementary value ... 

Continuous SARs. The set of factor Xa inhibitors discussed above presents a prime example of continuous SARs. As illustrated in Figure 4.7(a), many compounds show a high degree of structural diversity but have rather similar potency values and, in addition, similar compounds also have similar potency. These characteristics are reflected by a high SARI score of 0.80 produced by high continuity and low discontinuity scores, which is indicative of a continuous SAR. The continuity score of 0.71 reflects high intra-class structural diversity, whereas the discontinuity score of 0.12 indicates that similar ligands... 

Small values of the SAR index indicate discontinuous relationships between the activity and descriptors, large values indicate continuous, and intermediate values indicate heterogeneous relationships that combine continuous and discontinuous elements. 

Fig. 6. Enlarged fragment (25 km x 25 km) of the ERS-2 SAR image obtained on December 29, 1997, at 02 29 UTC showing the discontinuity of the oil spill by eddy-like structures near the Kuroshio boundary (copyright European Space Agency). The labels correspond to the labels in Figure 4...

This concluded an impressive and comprehensive SAR survey around the initial HTS hit through to a development candidate. Subsequent publications from the Merck group have indicated the compound to be hepatotoxic in predinical rat studies at elevated doses, implying a mechanism of mitochondrial inhibition and explaining the discontinuation of Merck A [58]. 

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