AbstractMotivationTo predict drug targets, graph-based machine-learning methods have been widely used to capture the relationships between drug, target and disease entities in drug–disease–target (DDT) networks. However, many methods cannot explicitly consider disease types at inference time and so will predict the same target for a given drug under any disease condition. Meanwhile, DDT networks are usually organized hierarchically carrying interactive relationships between involved entities, but these methods, especially those based on Euclidean embedding cannot fully utilize such topological information, which might lead to sub-optimal results. We hypothesized that, by importing hyperbolic embedding specifically for modeling hierarchical DDT networks, graph-based algorithms could better capture relationships between aforementioned entities, which ultimately improves target prediction performance.ResultsWe formulated the target prediction problem as a knowledge graph completion task explicitly considering disease types. We proposed FLONE, a hyperbolic embedding-based method based on capturing hierarchical topological information in DDT networks. The experimental results on two DDT networks showed that by introducing hyperbolic space, FLONE generates more accurate target predictions than its Euclidean counterparts, which supports our hypothesis. We also devised hyperbolic encoders to fuse external domain knowledge, to make FLONE enable handling samples corresponding to previously unseen drugs and targets for more practical scenarios.Availability and implementationSource code and dataset information are at:https://github.com/arantir123/DDT_triple_prediction.Supplementary informationSupplementary dataare available atBioinformatics Advancesonline.