Group graph: a molecular graph representation with enhanced performance, efficiency and interpretability

The exploration of chemical space holds promise for developing influential chemical entities. Molecular representations, which reflect features of molecular structure in silico, assist in navigating chemical space appropriately. Unlike atom-level molecular representations, such as SMILES and atom graph, which can sometimes lead to confusing interpretations about chemical substructures, substructure-level molecular representations encode important substructures into molecular features; they not only provide more information for predicting molecular properties and drug‒drug interactions but also help to interpret the correlations between molecular properties and substructures. However, it remains challenging to represent the entire molecular structure both intactly and simply with substructure-level molecular representations. In this study, we developed a novel substructure-level molecular representation and named it a group graph. The group graph offers three advantages: (a) the substructure of the group graph reflects the diversity and consistency of different molecular datasets; (b) the group graph retains molecular structural features with minimal information loss because the graph isomorphism network (GIN) of the group graph performs well in molecular properties and drug‒drug interactions prediction, showing higher accuracy and efficiency than the model of other molecular graphs, even without any pretraining; and (c) the molecular property may change when the substructure is substituted with another of differing importance in group graph, facilitating the detection of activity cliffs. In addition, we successfully predicted structural modifications to improve blood‒brain barrier permeability (BBBP) via the GIN of group graph. Therefore, the group graph takes advantages for simultaneously representing molecular local characteristics and global features.

Scientific contribution The group graph, as a substructure-level molecular representation, has the ability to retain molecular structural features with minimal information loss. As a result, it shows superior performance in predicting molecular properties and drug‒drug interactions with enhanced efficiency and interpretability.