One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through the Toll-like receptors (TLRs), which recognize specific molecular patterns that are present in microbial components (as lipopolysaccharides, LPS). Several new compounds interacting TLRs are now undergoing preclinical and clinical evaluation, for the treatment of sepsis and inflammatory diseases, cancer, and rheumatoid arthritis. Improvement in our understanding of the molecular mechanisms that mediate TLR signalling is of paramount importance to understand key aspects of immunity, with high potential to design new molecules able to modulate their functions.[1] TLR4, along with its accessory protein myeloid differentiation factor 2 (MD2), forms a heterodimeric complex (Figure 1, left), which specifically recognizes lipopolysaccharides (LPS),[2] and confers an intracellular signaling cascade that results in the inflammatory and immune response.
Molecular modelling techniques have been applied to the study of TLR4 interactions with reported agonists and antagonists such as taxanes (Figure 1, right), opioids, lipids A (with special focus on Burkholderia cepacia lipid A) and synthetic small molecules. Ligand-protein docking analysis has been carried out to unravel the details regarding molecular recognition processes. Our studies can be very valuable for the understanding of the interaction mechanism of these compounds, and for further design of new ligands able to modulate TLRs functions.
Figure 1. (left) TLR4-MD2 Complex with bound E. coli lipid A (PDB 3FXI); (right) Novel MD2 binding pose for paclitaxel.
[1] E. J. Hennessy, A. E. Parker, A. J. O'Neill. Targeting of Toll-like receptors: Emerging therapeutics? Nature Reviews Drug Discovery, 2010, 9, 293–307.
[2] B. S. Park, D. H. Song, H. M. Kim, B. S. Choi, H. Lee, J. O. Lee. The structural basis of lipopolysaccharide recognition by the TLR4-MD2 complex. Nature, 2009, 458, 1191-5.
