Thiopurine S-methyltransferase – An important intersection of drug-drug interactions in thiopurine treatment

Urbančič, Dunja (author), Jukič, Marko (author), Šmid, Alenka (author), Gobec, Stanislav (author), Jazbec, Janez (author), Mlinarič-Raščan, Irena (author)

Understanding the molecular mechanisms of medicines is crucial for developing novel drugs, for repurposing existing medicines, and for predicting toxicities. Thiopurine S-methyltransferase (TPMT) serves as an exemplary case in personalized medicine, as its activity is influenced by genetic variants, co-factors, substrates, and inhibitors, which lead to diverse outcomes in thiopurine therapy. This comprehensive review explores the role of TPMT in drug-drug interactions by investigating its interactions with co-factors, substrates, and inhibitors. We focus on the principal interactions of TPMT with clinically relevant inhibitors, and add to this information with molecular docking analyses for the substrate and co-factor binding sites of TPMT. Notably, methotrexate and sulfasalazine emerged as the top-ranked compounds with favorable docking scores for the co-factor binding site, while furosemide is presented as the highest ranked inhibitor for the substrate binding site. Furthermore, we highlight the chemical and structural properties governing ligand binding to TPMT. We support the molecular characteristics by using a summary of clinical implications. Examining the molecular interactions between substrates or inhibitors and TPMT not only addresses therapeutic consequences, but also reveals potential novel indications of interacting compounds. These insights are also invaluable for identifying endogenous ligands and enhancing our understanding of TPMT’s biological function.

• Language: English
• Keywords: thiopurine S-methyltransferase, drug-drug interactions, thiopurines, treatment outcome, molecular docking, methotrexate, allopurinol
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: 19 str.
• Numbering: Vol. 184, [article no.] 117893
• PID: 20.500.12556/RUL-167110
• UDC: 61-027.552:615
• ISSN on article: 0753-3322
• DOI: 10.1016/j.biopha.2025.117893
• COBISS.SI-ID: 225569283
• Publication date in RUL: 10.02.2025

Record is a part of a journal

• Title: Biomedicine & pharmacotherapy
• Shortened title: Biomed. pharmacother.
• Publisher: Elsevier Masson
• ISSN: 0753-3322
• COBISS.SI-ID: 25098240

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: tiopurin S-metiltransferaza, interakcije med zdravili, tiopurini, izid zdravljenja, molekularno združevanje, metotreksat, alopurinol, personalizirana medicina, zdravila