Application of shape-based and pharmacophore-based in silico screens for identification of Type II protein kinase inhibitors

The identification of new, potent and selective inhibitors of important protein kinase targets is a major goal of drug discovery. Here we analyze the crystal structures of 55 protein kinase complexes with Type II inhibitors and find they adopt a conserved twisted V-shape, with an angle of 121?±?8° and twist of 78?±?8°. The tightly conserved twist appears important in ensuring ligands curve around the protein backbone and towards the deep pocket. From this, we develop predictive pharmacophore- and shape-based screens to identify Type II inhibitors from a database which also contains Type I inhibitors as decoys. Both approaches exhibit a good level of discrimination for Type II molecules. The most effective pharmacophore model requires six features and three excluded volume regions. Shape-based screening using ROCS generally performs at least as well as pharmacophore approaches. There is only a moderate dependence of shape-based or pharmacophore-based screens on the underlying conformer generator (MOE, Macromodel, Omega and SPE), as well as on ligand linkage chemistry (amide and urea). Finally, we apply our approach to retrieval of Type II inhibitors from a modified version of the DUD database, containing over 104,000 compounds. We observe good enrichment, providing further evidence that the in silico screens developed here will constitute useful guides for identification of small molecule inhibitors targetting protein kinases in their inactive conformational state.     

Ab initio derivation of multi-orbital extended Hubbard model for molecular crystals

From configuration interaction (CI) ab initio calculations, we derive an effective two-orbital extended Hubbard model based on the gerade (g) and ungerade (u) molecular orbitals (MOs) of the charge-transfer molecular conductor (TTM-TTP)I(3) and the single-component molecular conductor [Au(tmdt)(2)]. First, by focusing on the isolated molecule, we determine the parameters for the model Hamiltonian so as to reproduce the CI Hamiltonian matrix. Next, we extend the analysis to two neighboring molecule pairs in the crystal and we perform similar calculations to evaluate the inter-molecular interactions. From the resulting tight-binding parameters, we analyze the band structure to confirm that two bands overlap and mix in together, supporting the multi-band feature. Furthermore, using a fragment decomposition, we derive the effective model based on the fragment MOs and show that the staking TTM-TTP molecules can be described by the zig-zag two-leg ladder with the inter-molecular transfer integral being larger than the intra-fragment transfer integral within the molecule. The inter-site interactions between the fragments follow a Coulomb law, supporting the fragment decomposition strategy.     

Aerodynamically assisted bio-jetting of hematopoietic stem cells

The research reported in this communication demonstrates the emerging direct cell handling technology now widely referred to as aerodynamically assisted bio-jetting. This is a non-electric field driven approach which directly competes with bio-electrosprays. The technology in these investigations has been explored for the direct handling of live murine primary hematopoietic stem cells. The viability studies demonstrate the complete inertness of this technology for handling such cells for a wide range of applications in both basic biology and clinical medicine. Interestingly these studies pave the way for this technology to undergo development as a flow cell for utility as a sheathless cell most useful in flow cytometry.     

Effect of alkali cation on irreversible gel formation in basic medium

This study is based on the understanding of the behavior of alkali silicates in a basic medium and aims to identify the mechanisms responsible for the formation of an irreversible gel and its consolidation. Commercial lithium, sodium and potassium silicate solutions were used to reveal the effect of the cation nature on the gelation process. Gels are obtained by acidifying alkaline silicate solutions with hydrochloric acid. A syneresis phenomenon during ripening that leads to the formation of a strongly consolidated solid has been observed. Whatever the cation, the gelation or syneresis mechanism would be similar. However, gelation time decreases and syneresis increases with the cation size. Gelation results from formation of small particles which grow in number and size and then gather to fill the available space. Ripening takes place through a dissolution/precipitation mechanism.     

Group Actions,k-Derivations,and Finite Morphisms

Let G be an affine algebraic group over an algebraically closed field k of characteristic zero. In this article, we consider finite G-equivariant morphisms F:X → Y of irreducible affine G-varieties. First we determine under which conditions on Y the induced map F ^G :X//G → Y//G of quotient varieties is also finite. This result is reformulated in terms of kernels of derivations on k-algebras A ? B such that B is integral over A. Second we construct explicitly two examples of finite G-equivariant maps F. In the first one, F ^G is quasifinite but not finite. In the second one, F ^G is not even quasifinite.     

Source identification in time domain electromagnetics

In this paper, we introduce two numerical methods to get an electric source that gives a specified electromagnetic field some time after the source starts emitting. The first one is called the Time Reversal Method (TRM) and originates from acoustics and the second one is called Linear Combination of Configuration Fields (LCCF) and consists in constructing and solving a linear problem in order to find a possible required source. In this paper, we show on 1D and 2D examples that the last method gives lower relative errors when compared with the time reversal method.     

Implementation of the type III seesaw model in FeynRules/MadGraph and prospects for discovery with early LHC data

We discuss the implementation of the “minimal” type III seesaw model, i.e. with one fermionic triplet, in FeynRules/MadGraph. This is the first step in order to realize a real study of LHC data recorded in the LHC detectors. With this goal in mind, we comment on the possibility of discovering this kind of new physics at the LHC running at 7 TeV with a luminosity of few fb⁻¹.     

Recent advances on the fast multipole accelerated boundary element method for 3D time-harmonic elastodynamics

This article is mainly devoted to a review on fast BEMs for elastodynamics, with particular attention on time-harmonic fast multipole methods (FMMs). It also includes original results that complete a very recent study on the FMM for elastodynamic problems in semi-infinite media. The main concepts underlying fast elastodynamic BEMs and the kernel-dependent elastodynamic FM-BEM based on the diagonal-form kernel decomposition are reviewed. An elastodynamic FM-BEM based on the half-space Green’s tensor suitable for semi-infinite media, and in particular on the fast evaluation of the corresponding governing double-layer integral operator involved in the BIE formulation of wave scattering by underground cavities, is then presented. Results on numerical tests for the multipole evaluation of the half-space traction Green’s tensor and the FMM treatment of a sample 3D problem involving wave scattering by an underground cavity demonstrate the accuracy of the proposed approach. The article concludes with a discussion of several topics open to further investigation, with relevant published work surveyed in the process.     

Controlled deposition of covalently bonded tantalum oxide on carbon supports by solvent evaporation sol-gel process

A simple strategy for covalently attaching Ta₂O₅ particles onto functionalized graphitic carbon supports has been developed to fabricate hybrid nanocomposites. In this process, tantalum ethoxide was directly reacted with functional groups on the carbon surface to form covalent bonding, which caused the carbonyl stretches of the carbon supports to be blue-shifted to 50-70 cm⁻¹ after Ta₂O₅ particle deposition. Homogeneously deposited Ta₂O₅ particles on the carbon supports have been studied by X-ray diffraction (XRD), FT-IR spectroscopy, scanning electron microscopy (SEM), and transmission electron microscope (TEM).