Toll-like receptors (TLRs) represent the first barrier in innate immune response and act as key players in the development of chronic inflammatory and autoimmune diseases. Thus, interest for identifying small organic molecules modulating TLRs has risen. In this study we present a virtual screening approach for the identification of novel TLR2 antagonists, combining ligand- and structure-based design.First, we performed a shape- and feature-based similarity search against commercially available compound collections, using TLR2 agonists from literature and two TLR2 antagonists previously identified in-house as query structures. Second, molecular interaction fields (MIFs) of the TLR2 binding site were calculated to derive a structure-based 3D pharmacophore that was then used for virtual screening.A selection of virtual screening hits was biologically tested in a cell-based assay for TLR2 inhibition, leading to several compounds with antagonistic activity (IC50) in the micromolar range.

Discovery of TLR2 antagonists by virtual screening

245th National Meeting (2013)

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