“Don’t blame the shopkeeper!!” Food, drink and confectionery advertising and British Government market controls during the Second World War

A novel series of \u3b2-lactam derivatives that was designed and synthesized to target RGD-binding and leukocyte integrins is reported. The compound library was evaluated by investigating the effects on integrin-mediated cell adhesion and cell signaling in cell lines expressing \u3b1v\u3b23, \u3b1v\u3b25, \u3b1v\u3b26, \u3b15\u3b21, \u3b1IIb\u3b23, \u3b14\u3b21, and \u3b1L\u3b22 integrins. SAR analysis of the new series of azetidinones enabled the recognition of structural elements associated with integrin selectivity. We obtained selective and potent agonists that could induce cell adhesion and promote cell signaling mediated by \u3b1v\u3b23, \u3b1v\u3b25, \u3b15\u3b21, or \u3b14\u3b21 integrin, and antagonists for the integrins \u3b1v\u3b23 and \u3b15\u3b21, as well as \u3b14\u3b21 and \u3b1L\u3b22, preventing the effects elicited by the respective endogenous agonists

A combined fragment-based virtual screening and STD-NMR approach for the identification of E-cadherin ligands

Cadherins promote cell-cell adhesion by forming homophilic interactions via their N-terminal extracellular domains. Hence, they have broad-ranging physiological effects on tissue organization and homeostasis. When dysregulated, cadherins contribute to different aspects of cancer progression and metastasis; therefore, targeting the cadherin adhesive interface with small-molecule antagonists is expected to have potential therapeutic and diagnostic value. Here, we used molecular docking simulations to evaluate the propensity of three different libraries of commercially available drug-like fragments (nearly 18,000 compounds) to accommodate into the Trp2 binding pocket of E-cadherin, a crucial site for the orchestration of the protein’s dimerization mechanism. Top-ranked fragments featuring five different aromatic chemotypes were expanded by means of a similarity search on the PubChem database (Tanimoto index >90%). Of this set, seven fragments containing an aromatic scaffold linked to an aliphatic chain bearing at least one amine group were finally selected for further analysis. Ligand-based NMR data (Saturation Transfer Difference, STD) and molecular dynamics simulations suggest that these fragments can bind E-cadherin mostly through their aromatic moiety, while their aliphatic portions may also diversely engage with the mobile regions of the binding site. A tetrahydro-β-carboline scaffold functionalized with an ethylamine emerged as the most promising fragment

Determination of the binding epitope of RGD-peptidomimetics to \u3b1v\u3b23 and \u3b1IIb\u3b23 integrin-rich intact cells by NMR and computational studies

NMR experiments (transferred NOE and Saturation Transfer Difference) were used to shed light on the binding epitope of RGD peptidomimetics 1-3 with integrins \u3b1v\u3b23 and \u3b1IIb\u3b23, expressed on the membrane of ECV304 bladder cancer cells and human platelets, respectively. The NMR results were supported by docking calculations in the active sites of \u3b1v\u3b23 and \u3b1IIb\u3b23 integrin receptors and were compared to the results of competitive \u3b1v\u3b23 receptor binding assays and competitive ECV304 cell adhesion experiments. While cis RGD ligand 1 interacts mainly with the \u3b1 integrin subunit through its basic guanidine group, trans RGD ligands 2 and 3 are able to interact with both the \u3b1 and \u3b2 integrin subunits via an electrostatic clam

Molecular dynamics simulation of aqueous solutions of glycine betaine

Molecular dynamics simulation is used to investigate the hydration properties of glycine betaine in a large range of solute concentration. Statistical analyses of the system trajectories evidence microscopic details suggesting an interpretation of experimental results recently obtained for aqueous solutions of trimethylamine-N-oxide, a bioprotectant closely related to glycine betaine

Molecular Dynamics Simulation of Aqueous Solutions of Trimethylamine-N-oxide and tert-Butyl Alcohol

In this work we have investigated hydration properties of aqueous solutions up to a solute molar fraction X2 = 0.125 of two isosteric molecules \u2013 the bioprotectant trimethylamine-N-oxide (TMAO) and the denaturant tert-butyl alcohol (TBA) \u2013 using molecular dynamics simulation at 298 K. Statistical analyses of the trajectories show in particular that as the solute concentration increases the number of the water molecules in the first hydration shell decreases uniformly for TMAO, while for TBA it decreases more rapidly in a concentration range where experiments indicate that TBA starts to self-aggregate. No appreciable solute segregation occurs for TMAO even in the most concentrated solution, where on the average each water molecule is shared by two solutes. This result parallels what has been recently found for glycine betaine, an organic osmolyte closely related to TMAO

Extremely localized molecular orbitals: theory and applications

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