Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 235, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114291
Keywords
Toll-like receptor 4; Inhibitors; Anti-in flammatory; Molecular docking
Categories
Funding
- China Postdoctoral Science Foundation [2019M661132]
- Doctoral Scientific Research Foundation of Liaoning Province [2019-BS-227]
- Major Basic Research Project of Natural Science Foundation of Shandong Province [ZR2018ZC1056]
- Taishan Industry Leading Talents Project [2018TSCYCX-17]
- Liaoning Revitalization Tal-ents Program [XLYC1908031]
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This review discusses TLR4 inhibitors that can bind directly to TLR4 or the TLR4/MD2 complex, as well as compounds that can downregulate the expression of TLR4. The involvement of specific residues in the binding of antagonistic ligands to the TLR4/MD2 complex provides useful information for structure-based TLR4 inhibitor design.
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. (c) 2022 Elsevier Masson SAS. All rights reserved.
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