{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T09:58:35Z","timestamp":1771840715832,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T00:00:00Z","timestamp":1771718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Program for Basic Research in the Russian Federation for a long-term period","award":["122030100170-5"],"award-info":[{"award-number":["122030100170-5"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The rapidly expanding body of biomedical literature encompasses a wealth of information concerning the pharmacological effects, mechanisms of action, adverse reactions, and repurposing potential of small-molecule therapeutics. Nevertheless, the systematic extraction and integration of this knowledge continue to pose substantial challenges. In this study, we propose an integrated text-mining framework for the automated extraction and structured representation of information on the biological activities of low-molecular-weight compounds, exemplified by angiotensin-converting enzyme (ACE) inhibitors as a representative pharmacological class. A corpus comprising over 20,000 PubMed titles and abstracts reporting in vitro, in vivo, and clinical investigations of ACE inhibitors was assembled. Chemical compounds, proteins\/genes, and diseases were recognized using a previously developed named entity recognition model based on conditional random fields. Entity-level associations were extracted at the sentence level through a rule-based approach employing manually curated pattern phrases, followed by normalization via automated queries to PubChem, UniProt, and the Human Disease Ontology. The proposed methodology facilitated the extraction of approximately 22,000 unique and normalized associations encompassing drug-target, drug-disease, and drug-drug relationships. In addition to confirming well-established therapeutic effects and clinically recognized drug combinations, the analysis identified underexplored pharmacological activities of ACE inhibitors, including antineoplastic, antifibrotic, and neuropsychiatric properties, along with mechanistic associations involving matrix metalloproteinases and neurotrophic signaling pathways. Collectively, these findings underscore the potential of automated literature mining to advance systematic knowledge integration and data-driven hypothesis generation in the contexts of drug repurposing and safety evaluation.<\/jats:p>","DOI":"10.3390\/ijms27042044","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T08:58:21Z","timestamp":1771837101000},"page":"2044","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Integrated Text Mining Approach for Discovering Pharmacological Effects, Drug Combinations, and Repurposing Opportunities of ACE Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"given":"Nadezhda Yu.","family":"Biziukova","sequence":"first","affiliation":[{"name":"Institute of Biomedical Chemistry, 10, Pogodinskaya Street, 119121 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7066-7925","authenticated-orcid":false,"given":"Polina I.","family":"Savosina","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Chemistry, 10, Pogodinskaya Street, 119121 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitry S.","family":"Druzhilovskiy","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Chemistry, 10, Pogodinskaya Street, 119121 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3723-7832","authenticated-orcid":false,"given":"Olga A.","family":"Tarasova","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Chemistry, 10, Pogodinskaya Street, 119121 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7937-2621","authenticated-orcid":false,"given":"Vladimir V.","family":"Poroikov","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Chemistry, 10, Pogodinskaya Street, 119121 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/bioinformatics\/16.8.747","article-title":"PASS: Prediction of Activity Spectra for Biologically Active Substances","volume":"16","author":"Lagunin","year":"2000","journal-title":"Bioinformatics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"372","DOI":"10.30895\/2312-7821-2023-11-4-372-389","article-title":"In Silico Estimation of the Safety of Pharmacologically Active Substances Using Machine Learning Methods: A Review","volume":"11","author":"Poroikov","year":"2023","journal-title":"Bezop. Risk Farmakoter."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tandra, G., Yoone, A., Mathew, R., Wang, M., Hales, C.M., and Mitchell, C.S. (2023). Literature-Based Discovery Predicts Antihistamines Are a Promising Repurposed Adjuvant Therapy for Parkinson\u2019s Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241512339"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1093\/bioinformatics\/btz682","article-title":"BioBERT: A Pre-Trained Biomedical Language Representation Model for Biomedical Text Mining","volume":"36","author":"Lee","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e11325","DOI":"10.15252\/msb.202211325","article-title":"Automated Assembly of Molecular Mechanisms at Scale from Text Mining and Curated Databases","volume":"19","author":"Bachman","year":"2023","journal-title":"Mol. Syst. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107","DOI":"10.26599\/BDMA.2023.9020007","article-title":"Identification of Proteins and Genes Associated with Hedgehog Signaling Pathway Involved in Neoplasm Formation Using Text-Mining Approach","volume":"7","author":"Biziukova","year":"2024","journal-title":"Big Data Min. Anal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1021\/acsomega.4c05723","article-title":"XenoMet: A Corpus of Texts to Extract Data on Metabolites of Xenobiotics","volume":"10","author":"Biziukova","year":"2025","journal-title":"ACS Omega"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1097\/00005344-198201000-00019","article-title":"Captopril Interferes with Neurogenic Vasoconstriction in the Pithed Rat by Angiotensin-Dependent Mechanisms","volume":"4","author":"Hatton","year":"1982","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_9","first-page":"390","article-title":"Effects of Enalapril Maleate on Blood Pressure, Renin-Angiotensin-Aldosterone System, and Peripheral Sympathetic Activity in Essential Hypertension","volume":"9","author":"Cerasola","year":"1987","journal-title":"Clin. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1136\/bmj.285.6356.1697","article-title":"Converting-Enzyme Inhibitor Enalapril (MK421) in Treatment of Hypertension with Renal Artery Stenosis","volume":"285","author":"Hodsman","year":"1982","journal-title":"Br. Med. J. (Clin. Res. Ed.)"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1161\/CIRCULATIONAHA.104.510461","article-title":"Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2","volume":"111","author":"Ferrario","year":"2005","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1440-1681.1988.tb01052.x","article-title":"Angiotensins II and III Prevent Captopril-Induced Renin Release in the Rat","volume":"15","author":"Moldenhauer","year":"1988","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.3317\/JRAAS.2004.019","article-title":"Angiotensin Inhibition in Heart Failure","volume":"5","author":"McMurray","year":"2004","journal-title":"J. Renin. Angiotensin. Aldosterone Syst."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1097\/01.hjh.0000220400.08128.fa","article-title":"Angiotensin Receptor Blockade with Candesartan in Heart Failure: Findings from the Candesartan in Heart Failure--Assessment of Reduction in Mortality and Morbidity (CHARM) Programme","volume":"24","author":"Ostergren","year":"2006","journal-title":"J. Hypertens. Suppl."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1053\/j.ajkd.2006.04.077","article-title":"Combination Therapy with an Angiotensin Receptor Blocker and an ACE Inhibitor in Proteinuric Renal Disease: A Systematic Review of the Efficacy and Safety Data","volume":"48","author":"MacKinnon","year":"2006","journal-title":"Am. J. Kidney Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1016\/j.clinthera.2007.09.019","article-title":"Effects of Renin-Angiotensin System Inhibition on End-Organ Protection: Can We Do Better?","volume":"29","author":"Weir","year":"2007","journal-title":"Clin. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s11886-020-01352-8","article-title":"Should Angiotensin-Converting Enzyme Inhibitors Ever Be Used for the Management of Hypertension?","volume":"22","author":"Turner","year":"2020","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_18","unstructured":"(2025, December 13). Ministry of Health of the Russian Federation, Available online: https:\/\/cr.minzdrav.gov.ru\/recomend\/62_2."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"F149","DOI":"10.1152\/ajprenal.00154.2021","article-title":"Therapeutic Effects of Lisinopril and Empagliflozin in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease","volume":"321","author":"Secher","year":"2021","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1097\/FJC.0000000000000077","article-title":"Imidapril and Enalapril Similarly Inhibit Plasma Matrix Metalloproteinase Activities and Attenuate Left Ventricular Remodeling in Patients With Acute Myocardial Infarction","volume":"63","author":"Yokota","year":"2014","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1254\/jphs.13040FP","article-title":"Significance of Matrix Metalloproteinase-9 Inhibition by Imidapril for Prevention of Abdominal Aortic Aneurysms in Angiotensin II Type 1 Receptor\u2013Knockout Mice","volume":"123","author":"Takai","year":"2013","journal-title":"J. Pharmacol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"106771","DOI":"10.1016\/j.clineuro.2021.106771","article-title":"Captopril Inhibits Matrix Metalloproteinase-2 and Extends Survival as a Temozolomide Adjuvant in an Intracranial Gliosarcoma Model","volume":"207","author":"Pinheiro","year":"2021","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_23","unstructured":"(2024, June 11). A Proof-of-Concept Clinical Trial Assessing the Safety of the Coordinated Undermining of Survival Paths by 9 Repurposed Drugs Combined with Metronomic Temozolomide (CUSP9v3 Treatment Protocol) for Recurrent Glioblastoma, Available online: https:\/\/clinicaltrials.gov\/study\/NCT02770378?cond=Cancer&intr=captopril&rank=6."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Riddiough, G.E., Fifis, T., Muralidharan, V., Christophi, C., Tran, B.M., Perini, M.V., and Vincan, E. (2024). Renin\u2013Angiotensin Inhibitor, Captopril, Attenuates Growth of Patient-Derived Colorectal Liver Metastasis Organoids. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063282"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Riddiough, G.E., Walsh, K.A., Fifis, T., Kastrappis, G., Tran, B.M., Vincan, E., Muralidharan, V., Christophi, C., Gordon, C.L., and Perini, M.V. (2022). Captopril, a Renin\u2013Angiotensin System Inhibitor, Attenuates Tumour Progression in the Regenerating Liver Following Partial Hepatectomy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095281"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3544","DOI":"10.1021\/acsabm.2c00486","article-title":"Cancer-Associated Fibroblast-Targeted Delivery of Captopril to Overcome Penetration Obstacles for Enhanced Pancreatic Cancer Therapy","volume":"5","author":"Chen","year":"2022","journal-title":"ACS Appl. Bio. Mater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e159254","DOI":"10.1172\/jci.insight.159254","article-title":"Hepatocellular Carcinoma Chemoprevention by Targeting the Angiotensin-Converting Enzyme and EGFR Transactivation","volume":"7","author":"Crouchet","year":"2022","journal-title":"JCI Insight"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Repova, K., Stanko, P., Baka, T., Krajcirovicova, K., Aziriova, S., Hrenak, J., Barta, A., Zorad, S., Reiter, R.J., and Adamcova, M. (2022). Lactacystin-Induced Kidney Fibrosis: Protection by Melatonin and Captopril. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.978337"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"326","DOI":"10.29252\/wjps.7.3.326","article-title":"Efficacy of Topical Enalapril in Treatment of Hypertrophic Scars","volume":"7","author":"Mohammadi","year":"2018","journal-title":"wjps"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.4077\/CJP.2011.AMM073","article-title":"Beneficial Effects of Enalapril on Chlorhexidine Digluconate-Induced Liver Peritoneal Fibrosis in Rats","volume":"54","author":"Lee","year":"2011","journal-title":"Chin. J. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.biopsych.2020.02.005","article-title":"Angiotensin-Converting Enzyme Inhibitor Rapidly Ameliorates Depressive-Type Behaviors via Bradykinin-Dependent Activation of Mammalian Target of Rapamycin Complex 1","volume":"88","author":"Luo","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.neuropharm.2018.03.011","article-title":"Antidepressant-like Effect of Losartan Involves TRKB Transactivation from Angiotensin Receptor Type 2 (AGTR2) and Recruitment of FYN","volume":"135","author":"Diniz","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ioannidis, J.P.A. (2022). Correction: Why Most Published Research Findings Are False. PLoS Med., 19.","DOI":"10.1371\/journal.pmed.1004085"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12651","DOI":"10.1021\/acs.jmedchem.2c01737","article-title":"Is Target-Based Drug Discovery Efficient? Discovery and \u201cOff-Target\u201d Mechanisms of All Drugs","volume":"66","author":"Sadri","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Pfeiffer, T., Bertram, L., and Ioannidis, J.P.A. (2011). Quantifying Selective Reporting and the Proteus Phenomenon for Multiple Datasets with Similar Bias. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018362"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Savosina, P., Druzhilovskiy, D., Filimonov, D., and Poroikov, V. (2024). WWAD: The Most Comprehensive Small Molecule World Wide Approved Drug Database of Therapeutics. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1473279"},{"key":"ref_37","unstructured":"(2025, December 31). Way2Drug\u2014Approved Drugs Database. Available online: https:\/\/way2drug.com\/dr\/ww_drug_approved.php."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"W612","DOI":"10.1093\/nar\/gkv352","article-title":"ChEMBL Web Services: Streamlining Access to Drug Discovery","volume":"43","author":"Davies","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"btae564","DOI":"10.1093\/bioinformatics\/btae564","article-title":"HunFlair2 in a Cross-Corpus Evaluation of Biomedical Named Entity Recognition and Normalization Tools","volume":"40","author":"Garda","year":"2024","journal-title":"Bioinformatics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"469","DOI":"10.18097\/pbmc20247006469","article-title":"Extracting Information on Virus-Human Interactions and on Antiviral Compounds Based on Automated Analysis of Large Text Collections","volume":"70","author":"Tarasova","year":"2024","journal-title":"Biomed. Khim."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"W563","DOI":"10.1093\/nar\/gky294","article-title":"An Update on PUG-REST: RESTful Interface for Programmatic Access to PubChem","volume":"46","author":"Kim","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"(2017). The UniProt Consortium UniProt: The Universal Protein Knowledgebase. Nucleic Acids Res., 45, D158\u2013D169.","DOI":"10.1093\/nar\/gkw1099"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"D1255","DOI":"10.1093\/nar\/gkab1063","article-title":"The Human Disease Ontology 2022 Update","volume":"50","author":"Schriml","year":"2022","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2044\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T08:59:59Z","timestamp":1771837199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2044"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,22]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27042044"],"URL":"https:\/\/doi.org\/10.3390\/ijms27042044","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,22]]}}}