Structure-activity and mechanistic relationships: the effect of chemical overlap on structural overlap in data bases...

Similarities between structures in SAR models derived from different data bases, termed 'structural overlap', can be used for determining mechanistic similarities, e.g., mutagenicity vs. carcinogenicity. However, the structural overlap may be affected by the proportion of common chemicals in the data bases, termed 'chemical overlap'. In order to refine our ability to determine mechanistic similarities, we investigated the relationship between chemical and structural overlap as well as the effect of the ratio of active to inactive chemicals and data base size on that relationship, using a data base of Salmonella mutagenicity. A linear relationship between chemical overlap and structural overlap with a slope of 0.332 was found. For data bases of 210, 300 and 390 chemicals, this relationship was consistent. Differences in ratios of active to inactive chemicals, i.e., 1:2, 1:1 and 2:1, did not appear to affect the linear model. We can use this relationship to adjust for chemical overlap when examining the structural overlap of data bases developed for different endpoints to determine the extent of mechanistic similarities.