Integrating concept of pharmacophore with graph neural networks for chemical property prediction and interpretation

Recently, graph neural networks (GNNs) have revolutionized the field of chemical property prediction and achieved state-of-the-art results on benchmark data sets. Compared with the traditional descriptor- and fingerprint-based QSAR models, GNNs can learn task related representations, which completely gets rid of the rules defined by experts. However, due to the lack of useful prior knowledge, the prediction performance and interpretability of the GNNs may be affected. In this study, we introduced a new GNN model called RG-MPNN for chemical property prediction that integrated pharmacophore information hierarchically into message-passing neural network (MPNN) architecture, specifically, in the way of pharmacophore-based reduced-graph (RG) pooling. RG-MPNN absorbed not only the information of atoms and bonds from the atom-level message-passing phase, but also the information of pharmacophores from the RG-level message-passing phase. Our experimental results on eleven benchmark and ten kinase data sets showed that our model consistently matched or outperformed other existing GNN models. Furthermore, we demonstrated that applying pharmacophore-based RG pooling to MPNN architecture can generally help GNN models improve the predictive power. The cluster analysis of RG-MPNN representations and the importance analysis of pharmacophore nodes will help chemists gain insights for hit discovery and lead optimization. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13321-022-00634-3.