Network module-based drug repositioning for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vascular remodeling leading to increased pulmonary vascular resistance and pulmonary arterial pressure. PAH is a highly morbid cardiopulmonary disease adversely affecting lifespan and quality of life. Despite increased awareness and advances of medical therapies in recent decades, long-term prognosis and survival remain poor for patients with PAH. Novel therapies that can target the underlying pathobiology of PAH and reverse pulmonary vascular remodeling are clearly needed. In this study, we develop a network module-based framework to examine potential drug repositioning for PAH. The rationale for this approach is that in order to have therapeutic effects, the targets of potential drugs must be significantly proximate to the disease module of interest in the human protein-protein interactome. Based on 15 existing drugs for treating PAH, our framework integrates drug-drug interactions, drug-drug chemical similarity, drug targets, and PAH disease proteins into the human interactome, and prioritizes candidate drugs for PAH. We identified 53 drugs that could potentially be repurposed for PAH. Many of these candidates have strong literature support. Compared to black-box-like machine learning models, network module-based drug repositioning can provide mechanistic insights into how repositioned drugs can target the underlying pathobiological mechanisms of PAH.