Heterogeneous SARs

SARI scores for 16 sets of active compounds used as reference classes for SARI calculations. The table is adapted from. The SARI scoring range of approximately 0.4-0.6 is considered intermediate and indicates the presence of heterogeneous 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. 

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.

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...

The very heterogeneous chemical structure of the compounds with MDR reversal activity has prevented structure-activity studies, although most MDR-inhibiting molecules share a basic structural pattern comprising a cationic protonable site linked to an aromatic lipophilic part by a spacer of variable length [61]. Structure-activity relationship (SAR) studies yielded only qualitative indications [62-64] unless very homogeneous series of molecules are studied [65]. 

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. 

Inhibitors of thromboxane synthase are an example of heterogeneous-relaxed SARs. The ligand spectrum includes diverse and highly potent inhibitors, similar to factor Xa, but also pairs of structurally similar inhibitors having very different potency (Figure 4.7c). In this case, the coexistence of continuous... 

Devillers J. QSAR modeling of large heterogeneous sets of molecules. SAR QSAR Environ Res 2001 12 515-28. 

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. 

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