title: Novel toll-like receptor 4 (TLR4) antagonists identified by structure- and ligand-based virtual screening.
abstract: Toll-like receptor 4 (TLR4) in complex with its accessory protein MD-2 represents an emerging target for the treatment of severe sepsis and neuropathic pain. We performed structure-based and ligand-based virtual screening targeting the TLR4-MD-2 interface. Three in silico hit compounds showed promising TLR4 antagonistic activities with micromolar IC50 values. These compounds also suppressed cytokine secretion by human peripheral blood mononuclear cells. The specific affinity of the most potent hit was confirmed by surface plasmon resonance direct-binding experiments. The results of our study represent a very promising starting point for the development of potent small-molecule antagonists of TLR4.
authors.affiliation: Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia.
authors.forename: Urban
authors.initials: U
authors.lastname: Švajger
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Matej
authors.initials: M
authors.lastname: Sova
authors.forename: Vesna
authors.initials: V
authors.lastname: Hodnik
authors.forename: Gregor
authors.initials: G
authors.lastname: Anderluh
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
chemical_list: D016207:Cytokines; D008024:Ligands; D054852:Small Molecule Libraries; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: Docking; HEK293; LPS; MD-2; PAMPs; PBMCs; PPI; PPRs; SEAP; SPR; Surface plasmon resonance; TLR4; TLR4 antagonist; TNF-α; Toll-like receptor 4; Virtual screening; human embryonic kidney 293 cells; lipopolysaccharide; myeloid differentiation factor 2; pathogen-associated molecular patterns; pattern-recognition receptor; peripheral blood mononuclear cells; protein–protein interaction; secreted embryonic alkaline phosphatase; surface plasmon resonance; toll-like receptor 4; tumor necrosis factor-α