Project information

• Status: not funded.

Toll-like receptors (TLR) are receptors of innate immunity that recognize pathogen-associated molecular patterns. They play a critical role in many pathological states, in acute and chronic inflammatory processes. We have been studying TLR9, TLR7 and TLR4 agonists and antagonists in recent years and several different projects by forming ligand-based models with ISE. All three have well-known activities associated with disease conditions: cancer, autoimmune disease, fungal, bacterial, viral infections, and more.

Our primary study used our ISE of TLR9 antagonists, screened 1.8 million molecules, and sent 60 top-scored candidates to cell-based testing of the antagonism at Fraunhofer IGB in Stuttgart. IC50 values of each of these top scored molecules were determined. Out of 60 molecules tested, 56 showed antagonistic activity. We discovered 21 new highly potential antagonists with IC50 values lower than 10 μM, with 5 of them having IC50 values under 1 μM.

A previous study using pharmacophore and docking to TLR4-MD2, we found candidates for blocking the associated sepsis reaction induced by TLR4 agonists, and have two candidates that are multitargeting TLR9 and TLR7 as antagonists.