Potentially repurposable drugs for schizophrenia identified from its interactome

• Published in: Scientific reports 2019-09, Vol.9 (1), p.12682-14, Article 12682
• Main Authors: Karunakaran, Kalyani B., Chaparala, Srilakshmi, Ganapathiraju, Madhavi K.
• Format: Article
• Language: English
• Subjects: 38; 631/114; 631/154; Acetazolamide - chemistry; Acetazolamide - metabolism; Acetazolamide - therapeutic use; Anticonvulsants - chemistry; Anticonvulsants - metabolism; Anticonvulsants - therapeutic use; Carbonic Anhydrases - chemistry; Carbonic Anhydrases - metabolism; Drug development; Drug Repositioning; Drugs; Etiology; Gene expression; Gene Expression Regulation; Genome-Wide Association Study; Humanities and Social Sciences; Humans; Hydroxycholecalciferols - chemistry; Hydroxycholecalciferols - metabolism; Hydroxycholecalciferols - therapeutic use; Mental disorders; multidisciplinary; Protein interaction; Protein Interaction Maps - genetics; Proteins; Receptors, Calcitriol - chemistry; Receptors, Calcitriol - metabolism; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - pathology; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-48307-w

We previously presented the protein-protein interaction network of schizophrenia associated genes, and from it, the drug-protein interactome which showed the drugs that target any of the proteins in the interactome. Here, we studied these drugs further to identify whether any of them may potentially be repurposable for schizophrenia. In schizophrenia, gene expression has been described as a measurable aspect of the disease reflecting the action of risk genes. We studied each of the drugs from the interactome using the BaseSpace Correlation Engine, and shortlisted those that had a negative correlation with differential gene expression of schizophrenia. This analysis resulted in 12 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for schizophrenia (disorder versus normal). Some of these drugs were already being tested for their clinical activity in schizophrenia and other neuropsychiatric disorders. Several proteins in the protein interactome of the targets of several of these drugs were associated with various neuropsychiatric disorders. The network of genes with opposite drug-induced versus schizophrenia-associated expression profiles were significantly enriched in pathways relevant to schizophrenia etiology and GWAS genes associated with traits or diseases that had a pathophysiological overlap with schizophrenia. Drugs that targeted the same genes as the shortlisted drugs, have also demonstrated clinical activity in schizophrenia and other related disorders. This integrated computational analysis will help translate insights from the schizophrenia drug-protein interactome to clinical research - an important step, especially in the field of psychiatric drug development which faces a high failure rate.