SAR base

The PASS estimations of biological activity spectra of new compounds are based on the Structure-Activity Relationships data and knowledge-base (SAR Base), which accumulates the results of the training set analysis. The in-house 

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The affinity of the various stabilized dipeptidyl prodrugs to hPepTl in Caco-2 cells was also investigated [42, 43, 50]. In the case of the D-Glu-Ala ester-linked benzyl alcohols, an improved hPepTl affinity with increasing drug lipophilicity was observed [50], Furthermore, these model prodrugs are transported trans-epithelially across Caco-2 cells by virtue of a hPepTl-mediated process [50]. Preliminary hPepTl affinity studies made on Asp-Sar- and Glu-Sar-based (model)-... 

The selectivity of the exchange between two cations is specific to saline snbsnr-face systems, described by the sodium adsorption ratio (SAR). Based on Na content in soil solutions, the U.S. Salinity Laboratory (U.S. Salinity Laboratory 1954) derived the equation... 

Indirect photoreaction rate constants (kox (total)) can be estimated using accepted values of average photooxidant concentrations ([Ox]avg) for R02,102, and HO and measured values for second-order rate constants (kox) for these oxidants with the compounds of interest. In many cases, reliable estimates of kox can be derived from simple SARs, based on the molecular structure of the compound. 

Lead refinement where sufficient information has been accumulated to use (Q)SAR-based design of compounds to achieve higher (optimal) efficacy and/or better property profiles. 

Integrating concentration- and effect-addition principles with (Q)SAR opens the door for (Q)SAR-based mixture assessments. As discussed above, linking interspecies correlations (Asfaw et al. 2004) with the USEPA s ECOSAR program allowed for the generation of species sensitivity distributions, hence a probabilistic estimate for aquatic community effects. Estimated HC5s for 4 chemicals were within a factor of 2 of published values, suggesting that current uncertainty factors overestimate NOECs established via data-based SSDs even SSDs derived... 

The main purpose of PASS is the prediction of activity spectra for new, possibly not yet synthesized compounds. Therefore, the general principle of the PASS algorithm is the exclusion from SAR Base of substances that is equivalent to the substance under prediction. So, if molecule n is equivalent to the molecule under prediction then this substance is excluded from sums in (Equations 6.17a,b). 

An example of prediction results for sulfathiazole is shown in Figure 6.6. This substance was found in SAR Base and was excluded from the SAR Base on prediction of its activity spectrum. The known (contained in SAR Base of PASS version 2007) activity spectrum includes the following activities antibacterial, antibiotic, dihydropteroate synthase inhibitor, iodide peroxidase inhibitor. In Figure 6.6 the predicted activity spectrum includes 65 of 374 pharmacological effects, 176 of 2755 molecular mechanisms, 7 of 50 side effects and toxicity, 11 of 121 metabolism terms at default Pa> Pi cutting points. All activities included in the SAR Base are predicted with Pa> Pi- The activity of as... 

Figure 6.6 Structure of sulfathiazole and part of its predicted activity spectrum. Activities contained in the SAR Base of PASS version 2007 are marked in bold.

For each kind of activity and each MNA descriptor the estimations of probabilities P Aj, P Ak Di) are calculated by Equations (6.17a,b). For each kind of activity Ak, for each p of TV active, and for each qoiN—Nk inactive compound in SAR Base, after excluding this compound, the estimates B p and B q are calculated. The Nk estimates of Bkp for active compounds are sorted in ascending order the N—Nk estimates of Bkq for inactive compounds are sorted in descending order. The functions FAk and F7 are calculated as conditional expectations ... 

In Figure 6.7 shows an example of probabilities PJ(B) and estimation as functions of B value, and in terms of Sensitivity, Specificity and Youden s index, for antihypertensive activity in the SAR Base of PASS version 2007. 

Figure 6.7 Estimations of probabilities Pa B) and PIB) as functions of B value a) and in terms of sensitivity, specificity and Youden s index b). The curves are obtained for activity antihypertensive based on data presented in SAR Base PASS version 2007.

In silico tools make a significant contribution to the SAR-based early identification of potential toxicity. An increasing volume of published preclinical and clinical toxicity data are collected and used to build structure-related searchable databases. These expert knowledge databases can analyze chemical structures and match them with potential mechanisms of toxicity. DEREK for Windows (Lhasa Ltd.)39 is one of such broadly used knowledge-based expert systems to provide toxicology alerts for new compounds. Although certainly not comprehensive, numerous efforts have been made to predict hepatotoxicity. Recently,... 

Benigni R, Zito R. Designing safer drugs (Q)SAR-based identification of mutagens and carcinogens. Curr Top Med Chem 2003 3 1289-300. 

TABLE 8. Some SPRS and SARS Based on Connectivity Indices... 

QSAR studies have become extremely useful towards understanding the toxic levels of bio-organisms. In this cmitext, various topological descriptors [158—160] are introduced to quantitatively correlate the hazardous effect of several chemical compounds on the ecosystem. The toxic effects of various compounds on fishes are reported in detail through fruitful SAR-based regression analyses [161—173]. 

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