Symmetric dithiodigalactoside: strategic combination of binding studies and detection of selectivity between a plant toxin and human lectins

Thioglycosides offer the advantage over O-glycosides to be resistant to hydrolysis. Based on initial evidence of this recognition ability for glycosyldisulfides by screening dynamic combinatorial libraries, we have now systematically studied dithiodigalactoside on a plant toxin (Viscum album agglutinin) and five human lectins (adhesion/growth-regulatory galectins with medical relevance e.g. in tumor progression and spread). Inhibition assays with surface-presented neoglycoprotein and in solution monitored by saturation transfer difference NMR spectroscopy, flanked by epitope mapping, as well as isothermal titration calorimetry revealed binding properties to VAA (Ka: 1560 ± 20 M-1). They were reflected by the structural model and the affinity on the level of toxin-exposed cells. In comparison, galectins were considerably less reactive, with intrafamily grading down to very minor reactivity for tandem-repeat-type galectins, as quantitated by radioassays for both domains of galectin-4. Model building indicated contact formation to be restricted to only one galactose moiety, in contrast to thiodigalactoside. The tested lycosyldisulfide exhibits selectivity between the plant toxin and the tested human lectins, and also between these proteins. Therefore, glycosyldisulfides have potential as chemical platform for inhibitor design

Computational Cancer Biology: An Evolutionary Perspective

ISSN:1553-734XISSN:1553-735

Shape: automatic conformation prediction of carbohydrates using a genetic algorithm

<p>Abstract</p> <p>Background</p> <p>Detailed experimental three dimensional structures of carbohydrates are often difficult to acquire. Molecular modelling and computational conformation prediction are therefore commonly used tools for three dimensional structure studies. Modelling procedures generally require significant training and computing resources, which is often impractical for most experimental chemists and biologists. <monospace>Shape</monospace> has been developed to improve the availability of modelling in this field.</p> <p>Results</p> <p>The <monospace>Shape</monospace> software package has been developed for simplicity of use and conformation prediction performance. A trivial user interface coupled to an efficient genetic algorithm conformation search makes it a powerful tool for automated modelling. Carbohydrates up to a few hundred atoms in size can be investigated on common computer hardware. It has been shown to perform well for the prediction of over four hundred bioactive oligosaccharides, as well as compare favourably with previously published studies on carbohydrate conformation prediction.</p> <p>Conclusion</p> <p>The <monospace>Shape</monospace> fully automated conformation prediction can be used by scientists who lack significant modelling training, and performs well on computing hardware such as laptops and desktops. It can also be deployed on computer clusters for increased capacity. The prediction accuracy under the default settings is good, as it agrees well with experimental data and previously published conformation prediction studies. This software is available both as open source and under commercial licenses.</p

VDA, a Method of Choosing a Better Algorithm with Fewer Validations

The multitude of bioinformatics algorithms designed for performing a particular computational task presents end-users with the problem of selecting the most appropriate computational tool for analyzing their biological data. The choice of the best available method is often based on expensive experimental validation of the results. We propose an approach to design validation sets for method comparison and performance assessment that are effective in terms of cost and discrimination power

Selenoglycosides in silico: ab initio-derived reparameterization of MM4, conformational analysis using histo-blood group ABH antigens and lectin docking as indication for potential of bioactivity

The identification of glycan epitopes such as the histo-blood group ABH determinants as docking sites for bacterial/viral infections and signals in growth regulation fuels the interest to develop non-hydrolysable mimetics for therapeutic applications. Inevitably, the required substitution of the linkage oxygen atom will alter the derivative's topology. Our study addresses the question of the impact of substitution of oxygen by selenium. In order to characterize spatial parameters and flexibility of selenoglycosides, we first performed ab initio calculations on model compounds to refine the MM4 force field. The following application of the resulting MM4R version appears to reduce the difference to ab initio data when compared to using the MM4 estimator. Systematic conformational searches on the derivatives of histo-blood group ABH antigens revealed increased flexibility with acquisition of additional low-energy conformer(s), akin to the behavior of S-glycosides. Docking analysis using the Glide program for eight test cases indicated potential for bioactivity, giving further experimental investigation a clear direction to testing Se-glycosides as lectin ligands