Abstract
Computational drug repositioning seeks to identify new therapeutic uses for existing or experimental drugs. Network-based methods are effective as they integrate relationships among drugs, diseases, and target proteins/genes into prediction models. However, traditional approaches often rely on a single phenotype-based disease similarity network, limiting the diversity of disease information. In this study, we constructed three disease similarity networks-phenotypic, ontological, and molecular-using data from OMIM, Human Phenotype Ontology annotations, and gene interaction network, respectively. These were integrated into disease multiplex networks and multiplex-heterogeneous networks. We applied a tailored Random Walk with Restart (RWR) algorithm to predict novel drug-disease associations. Experimental results show that both disease multiplex and multiplex-heterogeneous networks outperform their single-layer counterparts in leave-one-out cross-validation. Using 10-fold cross-validation, our method, MHDR, outperformed the state-of-the-art methods TP-NRWRH, DDAGDL and RGLDR, demonstrating the advantage of integrating multiple disease similarity networks. We predicted novel drug-disease associations by ranking candidates, identifying 68 associations supported by shared proteins/genes, 1,064 by shared pathways, and 84 by shared protein complexes, with many validated by clinical trials, underscoring the practical impact of our approach.