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Molecules 2016, 21(8), 994;

Computational Approaches to Toll-Like Receptor 4 Modulation

Department of Chemical & Physical Biology, Centro de Investigaciones Biológicas, CIB-CSIC, C/Ramiro de Maeztu 9, 28040 Madrid, Spain
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Academic Editors: James W. Gauld and Leif A. Eriksson
Received: 23 May 2016 / Revised: 22 July 2016 / Accepted: 22 July 2016 / Published: 30 July 2016
(This article belongs to the Special Issue Computational Design: A New Approach to Drug and Molecular Discovery)
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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. View Full-Text
Keywords: Toll-like receptor 4; TLR4/MD-2 modulators; molecular recognition; drug design; computational chemistry; MD simulations; docking; homology modeling; virtual screening Toll-like receptor 4; TLR4/MD-2 modulators; molecular recognition; drug design; computational chemistry; MD simulations; docking; homology modeling; virtual screening

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Billod, J.-M.; Lacetera, A.; Guzmán-Caldentey, J.; Martín-Santamaría, S. Computational Approaches to Toll-Like Receptor 4 Modulation. Molecules 2016, 21, 994.

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