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. 2019 Sep 3;9:12682. doi: 10.1038/s41598-019-48307-w

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Graphical abstract depicting the steps taken in this study to assess the biological validity of the shortlisted drugs. Drugs were extracted from the schizophrenia drug-protein interactome and screened for negative correlation of drug-induced versus disease-associated gene expression profiles. Drugs shortlisted in this manner were further checked for their toxicity, and eliminated if they were found to have harmful side effects. The targets of the remaining drugs and their network of protein-protein interactions were checked for their association with schizophrenia (SCZ)/other neuropsychiatric disorders (NPDs) using DisGeNET. Genes with opposite expression in drug-induced versus disease-associated profile were analyzed for their association with nervous system phenotypes (Mammalian Phenotype Ontology). Their networks were analyzed for enrichment of SCZ-associated pathways/GWAS traits. Apart from this, it was checked whether the shortlisted drugs are already being tested against NPDs (NIH Clinical Trials), and whether other drugs with the same targets show clinical activity in NPDs. Different sources of supporting information are shown by lines of different colors. Each of the drugs is also tagged with little squares of colors of corresponding supporting information. For example, amiloride is supported by “genes in network associated with neuropsychiatric disorders” (blue) and “in clinical trials for neuropsychiatric disorders” (bright pink). Acetazolamide, cinnarizine and tetracycline each are supported by 3 sources of supporting information.