Toll-like receptor 4 (TLR4) inhibitors: Current research and prospective

Toll-like receptor 4 (TLR4), a member of the Toll-like receptor (TLR) family, is involved in innate immunity and mediates inflammatory responses by recognizing lipopolysaccharide (LPS) or bacterial endotoxins. Hyperactivation of TLR4 triggers the production of various inflammatory factors, which are associated with the development of a variety of diseases, such as sepsis, endotoxemia, acute lung injury, rheumatoid arthritis, and cardiovascular diseases. And anti-inflammatory potential of TLR4 inhibitors have been validated. In this review, we discuss TLR4 inhibitors that can bind directly to TLR4 or the TLR4/MD2 complex, and provide a brief introduction to compounds that can downregulate the expression of TLR4. We focused on the possible modes by which the TLR4 inhibitors bind to the TLR4 or TLR4/MD2 complex. Three compounds targeting TLR4 have entered clinical trials, but unfortunately, two of them have been discontinued due to poor efficacy. Therefore, the discovery of effective small molecular compounds is the main research focus for TLR4 inhibitor design. In this review, by summarizing results from molecular dynamics simulation and molecular docking, we found that the Arg241 residue of TLR4 and the Tyr102, Ser120, and Lys122 residues of MD2 are involved in the binding of antagonistic ligands to the TLR4/MD2 complex; this is useful information for structure-based TLR4 inhibitor design. Toll-like receptor 4 (TLR4) could mediate inflammatory response by triggering the production of various proinflammatorymediators, which are associated with sepsis, endotoxemia, acute lung injury, rheumatoid arthritis and cardiovascular diseases. In this review, we will discuss TLR4 inhibitors which can bind directly to TLR4 or TLR4/MD2 complex. We will focus on the possible binding modes of TLR4 inhibitors with TLR4 or TLR4/MD2 complex. [Display omitted] •TLR4 inhibitors binding directly to TLR4 or TLR4/MD2 complex will be discussed.•A brief introduction of compounds downregulating the expression of TLR4.•Focusing on the binding modes of TLR4 inhibitors with TLR4 or TLR4/MD2 complex.