Identification of novel Interleukin-2 inhibitors through computational approaches
| Autor: | Sobia Ahsan Halim, M. Ahmed Mesaik, Omer Mohamed Abdalla, Maria Kontoyianni, Zaheer Ul-Haq, Abdul Wadood |
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| Rok vydání: | 2013 |
| Předmět: |
Interleukin 2
Cell Survival Stereochemistry T-Lymphocytes Gene Expression Quantitative Structure-Activity Relationship Biology Catalysis Cell Line Inorganic Chemistry Mice Drug Discovery medicine Animals Humans Physical and Theoretical Chemistry Cytotoxicity Molecular Biology Lymphokines Virtual screening Binding Sites Drug discovery Organic Chemistry Interleukin-2 Receptor alpha Subunit General Medicine High-Throughput Screening Assays Rats Molecular Docking Simulation Bovine kidney Docking (molecular) Interleukin-2 Cattle Mouse Fibroblast Databases Chemical Protein Binding Information Systems medicine.drug |
| Zdroj: | Molecular Diversity. 17:345-355 |
| ISSN: | 1573-501X 1381-1991 |
| DOI: | 10.1007/s11030-013-9431-4 |
| Popis: | Interleukin-2 (IL-2), is a 15.5-kDa cytokine that is now emerging as a target in drug discovery for novel therapeutic approaches in several autoimmune disorders. In an attempt to identify new inhibitors for the IL-2/IL-2R interaction, virtual screening (VS) was performed. Four different docking programs (GOLD, FlexX, Glide, and LigandFit) in combination with several scoring functions were used to identify novel IL-2/IL-2R interaction inhibitors. VS of a database of 6,000 compounds resulted in the identification of three novel and moderately active hits with IC $$_{50}$$ values ranging from 6.6 to 44.3 $$\upmu $$ M. Furthermore, the effect of these three compounds on the expression of IL-2R $$\alpha $$ was assessed. The three active hits showed dose-dependent inhibitory effects on the expression of IL-2R $$\alpha $$ with an IC $$_{50}$$ range of 5.8 to 140 $$\upmu $$ M. The cytotoxicity of these active hits was assessed using three normal cell-lines: bovine kidney cell-line (MDBK), mouse fibroblast cell-line (3T3), and rat hepatocytes cell-line (CC-1). The compounds were found to have negligible cytotoxicity compared to their IC $$_{50}$$ as IL-2/IL-2R interaction inhibitors. These results demonstrate that our VS protocol can identify novel inhibitors for IL-2/IL-2R interaction that effectively suppress IL-2 production, as well as the expression of IL-2R $$\alpha $$ . Optimization of these molecules could lead to improved and effective anti-inflammatory therapeutics. |
| Databáze: | OpenAIRE |
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