title: Computational design principles for bioactive dendrimer based constructs as antagonists of the TLR4-MD-2-LPS complex.
abstract: The cell surface interaction between bacterial lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) and MD-2 is central to bacterial sepsis syndromes and wound healing. We have shown that a generation (G) 3.5 polyamidoamine (PAMAM) dendrimer that was partially glycosylated with glucosamine inhibits TLR4-MD-2-LPS induced inflammation in a rabbit model of tissue scaring. However, it was a mixture of closely related chemical species because of the polydispersity of the starting PAMAM dendrimer. Generation 2 triazine dendrimers with single chemical entity material status are available at low cost and at the kilogram scale. PAMAM dendrimer can be synthetically grafted onto this triazine core dendrimer to make new triazine-PAMAM hybrid dendrimers. This led us to examine whether molecular modelling methods could be used to identify the key structural design principles for a bioactive lead molecule that could be synthesized and biologically evaluated. We describe our computer aided molecular studies of several dendrimer based constructs and the key design principles identified. Our approach should be more broadly applicable to the biologically focused, rational and accelerated design of molecules for other TLR receptors. They could be useful for treating infectious, inflammatory and malignant diseases.
authors.affiliation: Departments of Medicine, Infectious Diseases & Immunity, Imperial College London at Hammersmith Hospital, Ducane Road, London W12 ONN, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Barata
authors.forename: Ian
authors.initials: I
authors.lastname: Teo
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Lalwani
authors.forename: Eric
authors.initials: E
authors.lastname: Simanek
authors.forename: Mire
authors.initials: M
authors.lastname: Zloh
authors.forename: Sunil
authors.initials: S
authors.lastname: Shaunak
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D002921:Cicatrix / Q000378:metabolism*; D050091:Dendrimers; D004195:Disease Models, Animal; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011817:Rabbits; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001672:Biocompatible Materials; D050091:Dendrimers; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; C104700:PAMAM Starburst; D051197:Toll-Like Receptor 4