Compressing Chemistry Reveals Functional Groups

Journal article, 2026

We introduce the first formal large-scale assessment of the utility of traditional chemical functional groups as used in chemical explanations. Our assessment employs a fundamental principle from computational learning theory: a good compression of data should reveal a good explanation. We introduce an unsupervised learning algorithm based on the Minimum Message Length (MML) principle that searches for substructures that compress around three million biologically relevant molecules. We demonstrate that the discovered substructures contain most human-curated functional groups as well as novel larger patterns with more specific functions. We also run our algorithm on 24 specific bioactivity prediction data sets to discover data set-specific functional groups. Fingerprints constructed from data set-specific functional groups are shown to significantly outperform other fingerprint representations, including the MACCS and Morgan fingerprint, when training ridge regression models on bioactivity regression tasks.