title: Identification of novel Interleukin-2 inhibitors through computational approaches.
abstract: 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.VSof a database of 6,000compounds resulted in the identification of three novel and moderately active hits with IC50 values ranging from 6.6 to 44.3 μM. Furthermore, the effect of these three compounds on the expression of IL-2Rα was assessed. The three active hits showed dose-dependent inhibitory effects on the expression of IL-2Rα with an IC50 range of 5.8 to 140μM. 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).Thecompoundswere found to have negligible cytotoxicity compared to their IC50 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-2Rα. Optimization of these molecules could lead to improved and effective anti-inflammatory therapeutics.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Science, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Sobia Ahsan
authors.initials: SA
authors.lastname: Halim
authors.forename: Omer Mohamed
authors.initials: OM
authors.lastname: Abdalla
authors.forename: M Ahmed
authors.initials: MA
authors.lastname: Mesaik
authors.forename: Abdul
authors.initials: A
authors.lastname: Wadood
authors.forename: Zaheer
authors.initials: Z
authors.lastname: ul-Haq
authors.forename: Maria
authors.initials: M
authors.lastname: Kontoyianni
mesh_terms: D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D062126:Databases, Chemical; D055808:Drug Discovery; D015870:Gene Expression / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008222:Lymphokines / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D062105:Molecular Docking Simulation / Q000379:methods*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D008222:Lymphokines; C046147:interleukin 2 inhibitor