The outer membrane of Gram-negative bacteria includes lipopolysaccharides (LPS), among other constituents. Each LPS contains a bioactive lipid A moiety capable of binding a multitude of receptors involved in innate immune response signaling. LPS binds Toll-Like Receptor four (TLR4), as well as TLR4’s protein partners LBP, CD14 and MD-2 at high concentrations in vivo. Our focus is to elucidate the receptors putatively targeted by the lipid A analogs reported by our collaborators. Towards that goal, we docked known lipid A analogs and small molecules, whose targets are known, and concluded that Glide was the best performer. Subsequently, we carried out a series of docking experiments into human MD-2 and TLR4/MD-2 crystal structures and evaluated the resulting poses based on visual inspection, ranking, and critical residues. We present herein the receptors observed to be targeted by the analogs under investigation. Further, new synthetic targets are proposed in order to validate our predictions and the compounds therapeutic utility is considered for the development of a new human whole blood assay. Bioinformatics was employed to further characterize the human TLR4/MD-2 interface and evaluate the glycomes of human and mouse orthologs.
|Commitee:||Crider, Michael, Demchenko, Alexei, Nichols , Michael, Witt, Kenneth|
|School:||Southern Illinois University at Edwardsville|
|School Location:||United States -- Illinois|
|Source:||MAI 82/9(E), Masters Abstracts International|
|Subjects:||Biomedical engineering, Bioinformatics|
|Keywords:||Docking, Lipopolysaccharide, Protein-protein interactions (PPIs), Structure-based design, Toll-like receptor 4|
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