Representing chemical and enzymatic reactions in fingerprint space for applicability filtering and classification

Abstract Molecular and reaction fingerprints are widely used as static descriptors, but their relationship to graph-level reaction application remains unclear. We address this question in counted Extended-Connectivity Fingerprint (ECFP) space, representing reactions as signed differences between product and substrate fingerprints. We define ECFP-compatible templates, for which graph-level reaction application induces a constant fingerprint displacement, yielding a functorial mapping from graph transformations to affine translations in fingerprint space. We also introduce reaction-center ECFPs to encode the local environments required for template application and to provide a fast coordinate-wise prefilter for graph-level reaction applicability. We evaluate this framework on USPTO-50k and MetaNetX reactions across a range of ECFP radii. Both representations carry predictive information for reaction-class and enzyme-class classification, with reaction-center ECFPs contributing information not captured by reaction ECFPs alone. This framework connects reaction templates and reaction fingerprints to molecular pathway search and reaction-property prediction in fingerprint space.