A Computational Text-Mining Approach to Identify Potential Xerostomia Drug Targets

Objectives: Xerostomia (dry mouth) is a common condition of salivary gland hypofunction. The prevalence of this disorder has been estimated to be 5-46%. Risk factors include radiation therapy, autoimmune diseases, xerogenic medications, genetic predisposition, and diet. Molecular mechanisms associated with xerostomia etiology are poorly understood. Our objective was to (i) use a computational text-mining approach to review xerostomia and (ii) identify associated genes as candidate drug targets.
Methods: A conventional search was completed using PubMed and PMC to identify search terms relating to xerostomia and/or dry mouth. Each search term was subjected to text-mining completed by pubmed2ensembl analysis. GeneCodis online tool was used for enrichment and functional analysis of common genes between search terms for xerostomia and dry mouth. STRING online tool was used to analyze protein-protein interaction networks of genes involved in xerostomia (n=100) or dry mouth (n=50). Cytoscape^TM program was used to determine interactions of overlapping gene sets.
Results: We identified 66 search terms in common among xerostomia and dry mouth. Using genes identified by pubmed2ensembl as input, GeneCodis determined the cytokine-cytokine receptor interaction pathway (hsa04060) to be most significantly associated with the gene sets. STRING analysis confirmed the significance of cytokine ligands (e.g., chemokine ligand 3 [CCL3]) related to xerostomia, based on previous studies, and established the significance of CCL3 receptors, CCR1 and CCR5. Cytoscape^TM analysis determined that there were 44 genes in common at a confidence level of 0.98 between dry mouth and xerostomia networks including CCR5 with a STRING database score of 0.984. A protein-protein interaction of CCR5 with anti-inflammatory cytokine, interleukin 10 (IL-10) was also identified.
Conclusions: Xerostomia pathways were identified involving anti-inflammatory IL-10. Our findings suggest that CCL3, CCR1, CCR5, and IL-10 and/or associated pathways may be further investigated for validation and possible development of novel treatments for xerostomia/dry mouth.