A matched molecular pair (MMP) approach for selecting analogs suitable for structure activity relationship (SAR)-based read across.

ABSTRACT

One of the most challenging aspects of SAR-based read across is the identification of structurally similar compounds suitable for use as data sources to cover the safety of a target chemical. Matched molecular pair analysis (MMPA) provides a systematic method for mining experimental data for chemical substitutions that may be interpreted in terms of changes in properties. Here we use the relationships between structural substitutions linking a target chemical with an analog determined to be suitable using the expert-judgment based P&G framework of Wu et al. (2010). The relationships are established by applying MMPA to a database of compounds with safety assessed using SAR-based read across to suitable analogs possessing toxicological data. The analysis revealed that only five categories of substitutions per chemical class (aromatic or aliphatic) were necessary to link all molecular pairs. These data are summarized in a workflow outlining a strategy for searching toxicological databases for potential analogs. This approach provides structural comparisons that are interpretable and sensitive to small differences in the local structure of two compounds that may be linked to suitability for read across in contrast to the use of quantitative similarity measures which show little correlation with analog suitability.