Pharmacophore guided discovery of small-molecule interleukin 15 inhibitors
| Autor: | Szymon Niewieczerzal, Bartosz Trzaskowski, Magdalena Kowalewska, Małgorzata Dutkiewicz, Oliwia Zegrocka-Stendel, Slawomir Filipek, Katarzyna Koziak, Barbara Żyżyńska-Granica, Piotr Krzeczyński |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
In silico medicine.medical_treatment Pharmacology Peripheral blood mononuclear cell Small Molecule Libraries Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Drug Discovery medicine Humans Cephalosporin Antibiotic Interleukin-15 Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry General Medicine Small molecule 030104 developmental biology Cytokine Interleukin 15 030220 oncology & carcinogenesis Pharmacophore |
| Zdroj: | European Journal of Medicinal Chemistry. 136:543-547 |
| ISSN: | 0223-5234 |
| Popis: | Upregulation of interleukin 15 (IL-15) contributes directly i.a. to the development of inflammatory and autoimmune diseases. Selective blockade of IL-15 aimed to treat rheumatoid arthritis, psoriasis and other IL-15-related disorders has been recognized as an efficient therapeutic method. The aim of the study was to identify small molecules which would interact with IL-15 or its receptor IL-15Rα and inhibit the cytokine's activity. Based on the crystal structure of IL-15Rα·IL-15, we created pharmacophore models to screen the ZINC database of chemical compounds for potential IL-15 and IL-15Rα inhibitors. Twenty compounds with the highest predicted binding affinities were subjected to in vitro analysis using human peripheral blood mononuclear cells to validate in silico data. Twelve molecules efficiently reduced IL-15-dependent TNF-α and IL-17 synthesis. Among these, cefazolin - a safe first-generation cephalosporin antibiotic - holds the highest promise for IL-15-directed therapeutic applications. |
| Databáze: | OpenAIRE |
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