A Comparative Study of Cluster Detection Algorithms in Protein–Protein Interaction for Drug Target Discovery and Drug Repurposing

The interactions between drugs and their target proteins induce altered expression of genes involved in complex intracellular networks. The properties of these functional network modules are critical for the identification of drug targets, for drug repurposing, and for understanding the underlying mode of action of the drug. The topological modules generated by a computational approach are defined as functional clusters. However, the functions inferred for these topological modules extracted from a large-scale molecular interaction network, such as a protein–protein interaction (PPI) network, could differ depending on different cluster detection algorithms. Moreover, the dynamic gene expression profiles among tissues or cell types causes differential functional interaction patterns between the molecular components. Thus, the connections in the PPI network should be modified by the transcriptomic landscape of specific cell lines before producing topological clusters. Here, we systematically investigated the clusters of a cell-based PPI network by using four cluster detection algorithms. We subsequently compared the performance of these algorithms for target gene prediction, which integrates gene perturbation data with the cell-based PPI network using two drug target prioritization methods, shortest path and diffusion correlation. In addition, we validated the proportion of perturbed genes in clusters by finding candidate anti-breast cancer drugs and confirming our predictions using literature evidence and cases in the ClinicalTrials.gov. Our results indicate that the Walktrap (CW) clustering algorithm achieved the best performance overall in our comparative study.