Validating Natural Compounds as Toll-Like Receptor 4 (TLR4) Antagonists: Experimental Challenges and Therapeutic Perspectives

The activation of TLR4 by endogenous damage or danger-associated molecular patterns (DAMPs) suggested the use of TLR4 antagonists to target acute and chronic inflammatory diseases. In recent years, hundreds of natural compounds (NCs) have been screened for their activity as TLR4 antagonists. However, the direct interaction with TLR4 or TLR4/MD-2 dimer has not been proven for most of the natural molecules, and their mechanism of action has been only partially investigated. We review the recent literature on NCs active as TLR4 antagonists, analyzing the limitations and selecting among all candidates the compounds presenting new scaffolds desirable for drug development. After selecting a collection of representative hit structures, we also present novel docking calculations on TLR4/MD-2. Our analysis allowed the detection of common binding motifs in the receptor and the proposal of a structure–activity relationship from the ligands, enabling the discovery of new ligand scaffolds and pharmacophores for further development of drug hits.