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However, systematic studies on the effects of drugs on comorbidities are lacking. Drug interactions with the cellular protein\u2013protein interaction (PPI) network give rise to ADRs. We selected 6 comorbid disease pairs, identified the drugs used in the treatment of the individual diseases \u2018A\u2019 and \u2018B\u2019\u2013 44 drugs in anxiety and depression, 128 in asthma and hypertension, 48 in chronic obstructive pulmonary disease and heart failure, 58 in type 2 diabetes and obesity, 58 in Parkinson\u2019s disease and schizophrenia, and 84 in rheumatoid arthritis and osteoporosis\u2014and categorized them based on whether they aggravate the comorbid condition. We constructed drug target networks (DTNs) and examined their enrichment among genes in disease A\/B PPI networks, expressed across 53 tissues and involved in\u2009~\u20091000 pathways. To characterize the biological features of the DTNs, we performed principal component analysis and computed the Euclidean distance between DTN component scores and feature loading values. DTNs of disease A drugs not contraindicated in B were affiliated with proteins common to A\/B networks or uniquely found in the B network, similarly regulated common pathways, and disease-B specific pathways and tissues. DTNs of disease A drugs contraindicated in B were affiliated with common proteins or those uniquely found in the A network, differentially regulated common pathways, and disease A-specific pathways and tissues. Hence, DTN enrichment in pathways, tissues, and PPI networks of comorbid diseases will help identify drug contraindications in comorbidities.<\/jats:p>","DOI":"10.1007\/s13721-023-00440-3","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T02:50:11Z","timestamp":1710816611000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Drug contraindications in comorbid diseases: a protein interactome perspective"],"prefix":"10.1007","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1279-7750","authenticated-orcid":false,"given":"Kalyani B.","family":"Karunakaran","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhavi K.","family":"Ganapathiraju","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjeev","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samir K.","family":"Brahmachari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Balakrishnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"440_CR1","doi-asserted-by":"crossref","unstructured":"Alam A, Voronovich Z, Carley JA (2013) A review of therapeutic uses of mirtazapine in psychiatric and medical conditions. 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