Novel toll-like receptor 4 (TLR4) antagonists identified by structure- and ligand-based virtual screening

作者：Svajger Urban; Brus Boris; Turk Samo; Sova Matej; Hodnik Vesna; Anderluh Gregor; Gobec Stanislav^*

来源：European Journal of Medicinal Chemistry, 2013, 70: 393-399.

DOI：10.1016/j.ejmech.2013.10.019

• Toll-like receptor 4
• TLR4 antagonist
• Virtual screening
• Surface plasmon resonance
• Docking

Toll-like receptor 4 (TLR4) in complex with its accessory protein MD-2 represents an emerging target for the treatment of severe sepsis and neuropathic pain. We performed structure-based and ligand-based virtual screening targeting the TLR4 MD-2 interface. Three in si/ico hit compounds showed promising TLR4 antagonistic activities with micromolar IC50 values. These compounds also suppressed cytokine secretion by human peripheral blood mononuclear cells. The specific affinity of the most potent hit was confirmed by surface plasmon resonance direct-binding experiments. The results of our study represent a very promising starting point for the development of potent small-molecule antagonists of TLR4.

• 出版日期2013-12