TarIKGC: A Target Identification Tool Using Semantics-Enhanced Knowledge Graph Completion with Application to CDK2 Inhibitor Discovery

Target identification is a critical stage in the drug discovery pipeline. Various computational methodologies have been dedicated to enhancing the classification performance of compound-target interactions, yet significant room remains for improving the recommendation performance. To address this challenge, we developed TarIKGC, a tool for target prioritization that leverages semantics enhanced knowledge graph (KG) completion. This method harnesses knowledge representation learning within a heterogeneous compound-target-disease network. Specifically, TarIKGC combines an attention-based aggregation graph neural network with a multimodal feature extractor network to simultaneously learn internal semantic features from biomedical entities and topological features from the KG. Furthermore, a KG embedding model is employed to identify missing relationships among compounds and targets. In silico evaluations highlighted the superior performance of TarIKGC in drug repositioning tasks. In addition, TarIKGC successfully identified two potential cyclin-dependent kinase 2 (CDK2) inhibitors with novel scaffolds through reverse target fishing. Both compounds exhibited antiproliferative activities across multiple therapeutic indications targeting CDK2.