Computational Approaches to Toll-Like Receptor 4 Modulation

Abstract

Toll-like receptor 4 (TLR4), along with its accessory protein myeloid differentiation factor 2 (MD-2), builds a heterodimeric complex that specifically recognizes lipopolysaccharides (LPS), which are present on the cell wall of Gram-negative bacteria, activating the innate immune response. Some TLR4 modulators are undergoing preclinical and clinical evaluation for the treatment of sepsis, inflammatory diseases, cancer and rheumatoid arthritis. Since the relatively recent elucidation of the X-ray crystallographic structure of the extracellular domain of TLR4, research around this fascinating receptor has risen to a new level, and thus, new perspectives have been opened. In particular, diverse computational techniques have been applied to decipher some of the basis at the atomic level regarding the mechanism of functioning and the ligand recognition processes involving the TLR4/MD-2 system at the atomic level. This review summarizes the reported molecular modeling and computational studies that have recently provided insights into the mechanism regulating the activation/inactivation of the TLR4/MD-2 system receptor and the key interactions modulating the molecular recognition process by agonist and antagonist ligands. These studies have contributed to the design and the discovery of novel small molecules with promising activity as TLR4 modulators.

Toll-Like Receptor 4 Signalling and Its Impact on Platelet Function, Thrombosis, and Haemostasis

“…The lipid A moiety is localised in the outer cell membrane and is formed from a 1,4-bis-phosphorylated diglucosamine molecule linked to variable acyl chains (e.g., six chains in Escherichia coli LPS) [ 27 , 29 ]. The phosphate groups and acyl chains of LPS are important for interactions with TLR4, and alterations in these can shift the molecule from being an agonist to an antagonist [ 27 , 31 ]. LPS may not be the only ligand for TLR4 as damage-associated molecular patterns (DAMPs), such as high-mobility group box 1 (HMGB1) and heat shock proteins (HSPs), have also been suggested to be capable of inducing activation through this receptor [ 12 , 32 ].…”

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

“…In this regard, Mancek-Keber and Jerala [148] have proposed three postulates to distinguish direct agonists from indirect activators: (1) the agonist requires the TLR-4/MD-2 receptor complex; (2) either synthetically or in situ, they must activate the receptor complex in order to eliminate artefacts from other agonists; and (3) a specific molecular interaction between the agonist and TLR-4/MD-2 must be identified. Furthermore, in 2016 the group of Martin-Santamaria [149,150] proposed to use computational approaches [149] and big databases [150] for the identification of all atomic details in the TLR-4 receptor structure itself and the ligand-receptor interactions of different modulators to develop novel agonists and antagonists with promising biomedical applications, to reduce toxic effects, and improve drug-like properties, fine-tuning of relative potency of agonists and antagonists, binding capacity and specificity.…”

Collectins: Innate Immune Pattern Recognition Molecules

“…Studies have reported direct involvement of SP-A in TLR2 signalling, and inhibition of downstream gene activation (Murakami et al 2002). SP-A interacts directly with TLR4 and myeloid differentiation factor 2 (MD-2), which are known critical signalling receptors for LPS (Billod et al 2016). Thus, binding of SP-A with extracellular domain of TLR4 and MD-2 was revealed in a calcium-dependent manner, involving the CRD region.…”