Pharmacophore guided discovery of small-molecule interleukin 15 inhibitors.

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Zyzynska-Granica B, Trzaskowski B, Niewieczerzal S, Filipek S, Zegrocka-Stendel O, Dutkiewicz M, Krzeczynski P, Kowalewska M, Koziak K

Pharmacophore guided discovery of small-molecule interleukin 15 inhibitors.

Eur J Med Chem. 2017 Aug 18;136:543-547. doi: 10.1016/j.ejmech.2017.05.034. Epub 2017 May 12.

PubMed ID

28535470 [ View in PubMed

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Abstract

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-15Ralpha and inhibit the cytokine's activity. Based on the crystal structure of IL-15Ralpha.IL-15, we created pharmacophore models to screen the ZINC database of chemical compounds for potential IL-15 and IL-15Ralpha 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-alpha and IL-17 synthesis. Among these, cefazolin - a safe first-generation cephalosporin antibiotic - holds the highest promise for IL-15-directed therapeutic applications.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cefazolin	Interleukin-15	Protein	Humans	Unknown	Inhibitor	Details
Cefazolin	Interleukin-2	Protein	Humans	Unknown	Inhibitor	Details