HEDDI-Net: heterogeneous network embedding for drug-disease association prediction and drug repurposing, with application to Alzheimer's disease.

BACKGROUND

The traditional process of developing new drugs is time-consuming and often unsuccessful, making drug repurposing an appealing alternative due to its speed and safety. Graph neural networks (GCNs) have emerged as a leading approach for predicting drug-disease associations by integrating drug and disease-related networks with advanced deep learning algorithms. However, GCNs generally infer association probabilities only for existing drugs and diseases, requiring network re-establishment and retraining for novel entities. Additionally, these methods often struggle with sparse networks and fail to elucidate the biological mechanisms underlying newly predicted drugs.

METHODS

To address the limitations of traditional methods, we developed HEDDI-Net, a heterogeneous embedding architecture designed to accurately detect drug-disease associations while preserving the interpretability of biological mechanisms. HEDDI-Net integrates graph and shallow learning techniques to extract representative diseases and proteins, respectively. These representative diseases and proteins are used to embed the input features, which are then utilized in a multilayer perceptron for predicting drug-disease associations.

RESULTS

In experiments, HEDDI-Net achieves areas under the receiver operating characteristic curve of over 0.98, outperforming state-of-the-art methods. Rigorous recovery analyses reveal a median recovery rate of 73% for the top 100 diseases, demonstrating its efficacy in identifying novel target diseases for existing drugs, known as drug repurposing. A case study on Alzheimer's disease highlighted the model's practical applicability and interpretability, identifying potential drug candidates like Baclofen, Fluoxetine, Pentoxifylline and Phenytoin. Notably, over 40% of the predicted candidates in the clusters of commonly prescribed clinical drugs Donepezil and Galantamine had been tested in clinical trials, validating the model's predictive accuracy and practical relevance.

CONCLUSIONS

HEDDI-NET represents a significant advancement by allowing direct application to new diseases and drugs without the need for retraining, a limitation of most GCN-based methods. Furthermore, HEDDI-Net provides detailed affinity patterns with representative proteins for predicted candidate drugs, facilitating an understanding of their physiological effects. This capability also supports the design and testing of alternative drugs that are similar to existing medications, enhancing the reliability and interpretability of potential repurposed drugs. The case study on Alzheimer's disease further underscores HEDDI-Net's ability to predict promising drugs and its applicability in drug repurposing.