Effect of pH and ligand charge state on BACE-1 fragment docking performance

In this work we propose a protocol for estimating the effect of pH on the docking performance to BACE-1, which affords the charge state of the inhibitor as well as the protonation state of all ionisable residues in the protein at a given pH value. To the best of our knowledge, this is the first report of a protocol predicting the BACE-1 ligand docking poses not only at the neutral pH at which most crystallographic structures were obtained, but also at the optimal pH of the enzyme (in the acidic range), at which most of the BACE-1 binding affinity assays are performed. We have applied this protocol to a set of 23 fragment-like BACE-1 ligands that span four orders of magnitude in their binding affinities. The pK _a values of the BACE-1 acidic residues deviate substantially from the estimates for model compounds in solution and display a ligand dependent variability, especially in the case of the catalytic Asp dyad residues. This outcome should have a strong bearing on the design of protocols for docking based BACE-1 screening campaigns. Finally, we were able to find an explanation for the poor docking success rate of some fragments based on the availability of anchoring points, a rationale that could help to improve hit rates in BACE-1 screening campaigns.     

Complete assignment of NMR data of 22 phenyl‐1H‐pyrazoles' derivatives

Complete assignment of ¹H and ¹³C NMR chemical shifts and J(¹H/¹H and ¹H/¹⁹F) coupling constants for 22 1‐phenyl‐1H‐pyrazoles' derivates were performed using the concerted application of ¹H 1D and ¹H, ¹³C 2D gs‐HSQC and gs‐HMBC experiments. All 1‐phenyl‐1H‐pyrazoles' derivatives were synthesized as described by Finar and co‐workers. The formylated 1‐phenyl‐1H‐pyrazoles' derivatives were performed under Duff's conditions. Copyright © 2011 John Wiley & Sons, Ltd.     

Qualitative and quantitative analysis of new alkyl amide arginine surfactants by high-performance liquid chromatography and capillary electrophoresis.

A protocol for the qualitative and quantitative analysis of novel arginine-based cationic surfactants using HPLC and CE was studied and compared. The optimization of the analytical conditions was carried out through a systematic variation of the experimental parameters such as mobile phase, eluent conditions, ion pairing and amount of sample for HPLC, and type of buffer, ion strength, type and amount of organic solvent, sample injection time, applied voltage and column washing and conditioning for CE.     

Magnetic–fluorescent Langmuir–Blodgett films of fluorophore-labeled ferritin nanoparticles

We have covalently coupled fluorophore 4-(2-hydroxyethoxy)-7-nitro-2,1,3-benzoxadiazole (NBD) to the external ferritin shell through lysine residues. An increase in the luminescence quantum yield of the fluorescent ferritin particles and a blue shift in its emission peak compared to individual fluorophore were observed. The study of the particles by transmission electron microscopy showed that the native iron core ferritin is intact and that no degradation occurs during chemical functionalization of the protein shell. The NBD-labeled ferritin particles are water soluble, which allowed their controlled deposition by the Langmuir–Blodgett (LB) technique. Superparamagnetic and fluorescent properties of the particles are preserved within the LB film.     

Colloidal particles at fluid interfaces: Effective interactions, dynamics and a gravitation–like instability

Colloidal particles of micrometer size usually become irreversibly trapped at fluid interfaces if they are partially wetted by one phase. This opens the chance to create two–dimensional model systems where the effective interactions between the particles are possibly influenced by the presence of the interface to a great extent. We will review recent developments in the quantitive understanding of these effective interactions with a special emphasis on electrostatics and capillarity. Charged colloids of micrometer size at an interface form effective dipoles whose strength sensitively depends on the double layer structure. We discuss the success of modified Poisson–Boltzmann equations with regard to measured colloidal dipole moments. On the other hand, for somewhat larger particles capillary interactions arise which are long–ranged and analogous to two–dimensional screened Newtonian gravity with the capillary length λ as the screening length. For colloidal diameters of around 10 micrometer, the collective effect of these long–ranged capillary interactions will dominate thermal motion and residual, short–ranged repulsions, and results in an instability towards a collapsed state for a finite patch of particles. Such long–ranged interactions with the associated instability are also of interest in other branches of physics, such as self-gravitating fluids in cosmology, two–dimensional vortex flow in hydrodynamics, and bacterial chemotaxis in biology. Starting from the colloidal case we develop and discuss a dynamical “phase diagram” in the temperature and interaction range variables which appears to be of more general scope and applicable also to other systems.     

Evaluation of adaptive mesh refinement and coarsening for the computation of compressible flows on unstructured meshes

The compressible gas flows of interest to aerospace applications often involve situations where shock and expansion waves are present. Decreasing the characteristic dimension of the computational cells in the vicinity of shock waves improves the quality of the computed flows. This reduction in size may be accomplished by the use of mesh adaption procedures. In this paper an analysis is presented of an adaptive mesh scheme developed for an unstructured mesh finite volume upwind computer code. This scheme is tailored to refine or coarsen the computational mesh where gradients of the flow properties are respectively high or low. The refinement and coarsening procedures are applied to the classical gas dynamic problems of the stabilization of shock waves by solid bodies. In particular, situations where oblique shock waves interact with an expansion fan and where bow shocks arise around solid bodies are considered. The effectiveness of the scheme in reducing the computational time, while increasing the solution accuracy, is assessed. It is shown that the refinement procedure alone leads to a number of computational cells which is 20% larger than when alternate passes of refinement and coarsening are used. Accordingly, a reduction of computational time of the same order of magnitude is obtained. Copyright © 2005 John Wiley & Sons, Ltd.     

Heck reactions in monoglyme and diglyme using BmimCl as pre‐ligand

Heck reactions between iodobenzene and methyl acrylate were carried out in monoglyme and diglyme as solvents, using different ligands and palladium sources, and good to high yields were obtained in the production of (E)‐substituted olefins. The ionic liquid BmimCl was successfully utilized as pre‐ligand to substitute triphenylphosphine. Copyright © 2007 John Wiley & Sons, Ltd.     

Truncations of multilinear Hankel operators

We extend to multilinear Hankel operators the fact that some truncations of bounded Hankel operators are still bounded. We prove and use a continuity property of bilinear Hilbert transforms on products of Lipschitz spaces and Hardy spaces.