chemical database curators

Abstract: Molecular representations such as fingerprints and learned embeddings play a central role in cheminformatics and small-molecule machine learning. They serve as the primary input for a diverse array of tasks, including clustering, dataset splitting, and virtual screening, yet their evaluation is often limited to downstream model performance on narrow benchmark tasks. We carried out a systematic investigation of the quality of molecular representations, finding that none of the state-of-the-art molecular embedding models capture graph structure, 3D shape, or ADMET endpoint similarity better than fingerprints or physicochemical descriptors. However, classical fingerprints also revealed their own material limitations. For example, we show that depending on the representation, between 225M and $\sim$4B molecules have non-unique representations in the 10.8B Enamine REAL database, with implications for virtual screening. Our findings provide an insight into the current limitations of molecular representations, outlining future research directions for the development of more robust encodings of small molecules.

Abstract: A virtual screening campaign may produce thousands of promising candidates, but only a small number can be purchased, synthesized, or tested. The practical question is how to select a set of compounds that both rank well and are diverse enough: this poses a genuine tradeoff, where selecting the highest-scoring molecules yields limited diversity, while diversity selection sacrifices some well-scoring molecules. We introduce OPDiv, a diversity selection and evaluation algorithm solving this tradeoff by finding an optimal subset of molecules using integer optimization. We demonstrate the selection algorithm in practice with fingerprint distance, shape and electrostatic diversity and compare the resulting diversity spectra. We argue that virtual screening is not merely a ranking problem, but also an implicit constrained optimization task: when redundant chemotypes are undesirable, pipelines should be compared based on the top-k compound selections satisfying the desired diversity constraints. OPDiv makes it possible to find the optimal compound set under a given diversity threshold efficiently and serves as a fair benchmark of the best diverse selection achievable by a given structure-based or ligand-based virtual screening pipeline, molecular search or generative model.