-A New, Extensible Set of Molecular Substructures for QSAR/QSPR and Read-Across Predictions

Molecular structure-based predictive models provide a proven alternative to costly and inefficient animal testing. However, due to a lack of interpretability of predictive models built with abstract molecular descriptors they have earned the notoriety of being black boxes. Interpretable models require interpretable descriptors to provide chemistry-backed predictive reasoning and facilitate intelligent molecular design. We developed a novel set of extensible chemistry-aware substructures, , to support interpretable predictive models and read-across protocols. Performance of in chemical characterization and search for structurally similar actives for read-across applications was compared with four publicly available fingerprint sets (MACCS (166), PubChem (881), ECFP4 (1024), ToxPrint (729)) in three benchmark sets (MUV, ULS, and Tox21) spanning ∼145 000 compounds and 78 molecular targets at 1%, 2%, 5%, and 10% false discovery rates. In 18 of the 20 comparisons, interpretable features performed better than the publicly available, but less interpretable and fixed-bit length, fingerprints. Examples are provided to show the enhanced capability of in extracting compounds with higher scaffold similarity. features are interpretable and efficiently characterize diverse chemical collections, thus making them a better choice for building interpretable predictive models and read-across protocols.