Design of new plasmepsin inhibitors: a virtual high throughput screening approach on the EGEE grid

Though different species of the genus Plasmodium may be responsible for malaria, the variant caused by P. falciparum is often very dangerous and even fatal if untreated. Hemoglobin degradation is one of the key metabolic processes for the survival of the Plasmodium parasite in its host. Plasmepsins, a family of aspartic proteases encoded by the Plasmodium genome, play a prominent role in host hemoglobin cleavage. In this paper we demonstrate the use of virtual screening, in particular molecular docking, employed at a very large scale to identify novel inhibitors for plasmepsins II and IV. A large grid infrastructure, the EGEE grid, was used to address the problem of large computation resources required for docking hundreds of thousands of chemical compounds on different plasmepsin targets of P. falciparum. A large compound library of about 1 million chemical compounds was docked on 5 different targets of plasmepsins using two different docking software, namely FlexX and AutoDock. Several strategies were employed to analyze the results of this virtual screening approach including docking scores, ideal binding modes, and interactions to key residues of the protein. Three different classes of structures with thiourea, diphenylurea, and guanidino scaffolds were identified to be promising hits. While the identification of diphenylurea compounds is in accordance with the literature and thus provides a sort of "positive control", the identification of novel compounds with a guanidino scaffold proves that high throughput docking can be effectively used to identify novel potential inhibitors of P. falciparum plasmepsins. Thus, with the work presented here, we do not only demonstrate the relevance of computational grids in drug discovery but also identify several promising small molecules which have the potential to serve as candidate inhibitors for P. falciparum plasmepsins. With the use of the EGEE grid infrastructure for the virtual screening campaign against the malaria causing parasite P. falciparum we have demonstrated that resource sharing on an eScience infrastructure such as EGEE provides a new model for doing collaborative research to fight diseases of the poor.     

Time-resolved Laue diffraction of deforming micropillars

We demonstrate real-time resolved white beam Laue diffraction during compression of micron-sized focused ion beam milled single crystals Au pillars, revealing the dynamical correlation between microstructure and plasticity. The evolution of the Laue patterns of the Au pillars demonstrates the occurrence of crystal rotation and strengthening is explained by plasticity starting on a slip system that is geometrically not predicted but selected because of the character of the preexisting strain gradient.     

Syntheses and structures of three complexes of formulas [L3Co(μ2-O2P(Bn)2)3CoL'][L"], featuring octahedral and tetrahedral cobalt(II) geometries; variable-temperature magnetic susceptibility measurement and analysis on [(py)3Co(μ2-O2PBn2)3Co(py)][ClO4

The syntheses and structural properties of three dinuclear complexes [L(3)Co(μ(2)-O(2)P(Bn)(2))(3)CoL'][L"] [one ionic L(3) = py(3), L' = py, L" = ClO(4)(-) (1) and two molecular L(3) = py(3), L' = Cl (2) and L(3) = py, μ(2)-NO(3)(-), L' = py (3)] are reported. Complexes feature octahedral Co(II) sites bridged by three dibenzylphosphinate ligands to a tetrahedrally ligated Co(II) site, with the remaining coordination sites occupied by py, nitrato, and Cl ligands. The Co-Co distances are 4.248 ? at 291 K and 4.265 ? at 100 K for 1 and 4.278 and 4.0313(7) ? for 2 and 3, respectively at 100 K. A fit of the low-temperature magnetic susceptibility data was derived for complex 1 with g = 2.25, TIP = 700 × 10(-6) cm(3) mol (-1), λ = -173 cm(-1), κ = 0.93, ν = -3.9, Δ = 630 cm(-1), J = 0.15 cm(-1), and θ = -1.8 resulting in R(χ(M)) = 2.5 × 10(-5) and R(χ(M)T) = 5.8 × 10(-5).     

Topology-Preserving Geodesic Active Contours for Segmentation of High Content Fluorescent Cellular Images

In this paper a method for segmentation of fluorescent cellular images is introduced, which uses geodesic active contours. After segmentation of the nuclei by a thresholding algorithm, the appropriate whole cells are detected by inflation of the nuclei masks and gradient information. Because the implicit level set formulation provides topological changes and the topology of the nuclei and the whole cells is equal, a topology–preserving modification is necessary. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Reconstruction of Wideband Reflectivity Densities by Wavelet Transforms

This paper is concerned with reconstruction problems arising in the context of radar signal analysis. The goal in radar is to obtain information about objects by emitting certain signals and analyzing the reflected echoes. In this paper, we shall focus on the general wideband model for radar echoes and on the case of continuously distributed objects D (reflectivity density). In this case, the echo is given by an inverse wavelet transform of the density D where the role of the analyzing wavelet is played by the transmitted signal. However, the null space of an inverse wavelet transform is nontrivial, it is described by the corresponding reproducing kernel. Following the approach of Naparst [14] and Rebolla-Neira et al. [16], we suggest to treat this problem by transmitting not just one signal but a family of signals. Indeed, a reconstruction formula for one- and 2-dimensional reflectivity densities can be derived, provided that the set of outgoing signals forms an orthogonal basis or – more general – a frame. We also present some rigorous error estimates for these reconstruction formulas. The theoretical results are confirmed by some numerical examples.     

Überblick über die Phosphide des Strontiums

The method of the reaction in a stainless steel cube which was used for the first time in the preparation of barium phosphides is also applicable to phosphide-producing mixtures of strontium and phosphorus. In connection with high temperature experiments it served to obtain a survey of the binary system strontium—phosphorus. This binary system is largely analogous to the binary system barium—phosphorus. The compounds found were: “Sr₂P”, Sr₃P₂, Sr₄P₃? Sr_1,1P, SrP, Sr₄P₅ and SrP². The strontium-rich phosphides have melting or decomposing temperatures which are higher than those of the analogous barium phosphides. The powders of Sr₃P₂, Sr₄P₃ and SrP are brown to blackviolet. Sr₃P₂ cristallizes isostructurally with Ba₃P₂. Some properties indicate that the bonding is more ionic than in Ba₃P₂. The structural relationship of the alkaline earth pnietides with the lanthanide chalogenides is discussed. Sr₃P₂ and Ba₃P₂ complete the inverse isostructures of these compounds.     

Internal friction and vulnerability of mixed alkali glasses

Based on a hopping model we show how the mixed alkali effect in glasses can be understood if only a small fraction c(V) of the available sites for the mobile ions is vacant. In particular, we reproduce the peculiar behavior of the internal friction and the steep fall ("vulnerability") of the mobility of the majority ion upon small replacements by the minority ion. The single and mixed alkali internal friction peaks are caused by ion-vacancy and ion-ion exchange processes. If c(V) is small, they can become comparable in height even at small mixing ratios. The large vulnerability is explained by a trapping of vacancies induced by the minority ions. Reasonable choices of model parameters yield typical behaviors found in experiments.