Maximum common binding modes (MCBM): consensus docking scoring using multiple ligand information and interaction fingerprints

Improving the scoring functions for small molecule-protein docking is a highly challenging task in current computational drug design. Here we present a novel consensus scoring concept for the prediction of binding modes for multiple known active ligands. Similar ligands are generally believed to bind to their receptor in a similar fashion. The presumption of our approach was that the true binding modes of similar ligands should be more similar to each other compared to false positive binding modes. The number of conserved (consensus) interactions between similar ligands was used as a docking score. Patterns of interactions were modeled using ligand receptor interaction fingerprints. Our approach was evaluated for four different data sets of known cocrystal structures (CDK-2, dihydrofolate reductase, HIV-1 protease, and thrombin). Docking poses were generated with FlexX and rescored by our approach. For comparison the CScore scoring functions from Sybyl were used, and consensus scores were calculated thereof. Our approach performed better than individual scoring functions and was comparable to consensus scoring. Analysis of the distribution of docking poses by self-organizing maps (SOM) and interaction fingerprints confirmed that clusters of docking poses composed of multiple ligands were preferentially observed near the native binding mode. Being conceptually unrelated to commonly used docking scoring functions our approach provides a powerful method to complement and improve computational docking experiments.     

Antioxidant activity assays on-line with liquid chromatography

Screening for antioxidants requires simple in vitro model systems to investigate antioxidant activity. High resolution screening (HRS), combining a separation technique like HPLC with fast post-column (bio)chemical detection can rapidly pinpoint active compounds in complex mixtures. In this paper both electrochemical and chemistry-based assays are reviewed and discussed. The focus is on the mechanisms involved and differences between the assays, rather than on the matrix or analytes. With 45 applications high resolution antioxidant screening has now become an almost routine tool for the rapid identification of antioxidants in plant extracts, foods and beverages. The methods based on true reactive oxygen species (ROS) provide the most realistic measure of antioxidant activity. Unfortunately these methods are difficult to set up and control and have not been applied since they were reported. The methods based on electrochemical detection are more practical, but have still received only limited attention for practical screening purposes. The methods based on a single relatively stable reagent such as DPPH and ABTS(+) have become most popular, because of their simple set-up and ease of control. The methods have been combined with on-line DAD, MS and NMR detection for rapid identification of active constituents.     

Quivers with potentials and their representations I: Mutations

We study quivers with relations given by noncommutative analogs of Jacobian ideals in the complete path algebra. This framework allows us to give a representation-theoretic interpretation of quiver mutations at arbitrary vertices. This gives a far-reaching generalization of Bernstein–Gelfand–Ponomarev reflection functors. The motivations for this work come from several sources: superpotentials in physics, Calabi–Yau algebras, cluster algebras.      

Rank decomposition in zero pattern matrix algebras

For a block upper triangular matrix, a necessary and sufficient condition has been given to let it be the sum of block upper rectangular matrices satisfying certain rank constraints; see H.Bart, A.P.M.Wagelmans (2000). The proof involves elements from integer programming and employs Farkas’ lemma. The algebra of block upper triangular matrices can be viewed as a matrix algebra determined by a pattern of zeros. The present note is concerned with the question whether the decomposition result referred to above can be extended to other zero pattern matrix algebras. It is shown that such a generalization does indeed hold for certain digraphs determining the pattern of zeros. The digraphs in question can be characterized in terms of forests, i.e., disjoint unions of rooted trees.     

Optical imaging of pattern formation: reflection anisotropy microscopy applied to globally coupled oscillatory CO-oxidation

A reflection anisotropy microscope (RAM) creates the contrast in its images from a change in the polarization orientation of reflected light from a surface. This may stem from local variations of the reconstruction of a surface, being initiated by changes in an adsorption layer. The advantages and disadvantages of a recently improved RAM versus other optical imaging techniques are discussed. We demonstrate the unique features of RAM and present the first experimental findings of so called 2pi phase kinks in the globally coupled CO-oxidation on Pt(110).     

Synthesis of Functional Polymers by Post‐Polymerization Modification

Post‐polymerization modification is based on the direct polymerization or copolymerization of monomers bearing chemoselective handles that are inert towards the polymerization conditions but can be quantitatively converted in a subsequent step into a broad range of other functional groups. The success of this method is based on the excellent conversions achievable under mild conditions, the excellent functional‐group tolerance, and the orthogonality of the post‐polymerization modification reactions. This Review surveys different classes of reactive polymer precursors bearing chemoselective handles and discusses issues related to the preparation of these reactive polymers by direct polymerization of appropriately functionalized monomers as well as the post‐polymerization modification of these precursors into functional polymers.     

The Order Completion Method for Systems of Nonlinear PDEs Revisited

In this paper we presents further developments regarding the enrichment of the basic Theory of Order Completion as presented in Oberguggenberger and Rosinger (Solution of continuous nonlinear PDEs through order completion, North-Holland, Amsterdam, 1994). In particular, spaces of generalized functions are constructed that contain generalized solutions to a large class of systems of continuous, nonlinear PDEs. In terms of the existence and uniqueness results previously obtained for such systems of equations (van der Walt, Acta Appl. Math. 103:1–17, 2008), one may interpret the existence of generalized solutions presented here as a regularity result. Furthermore, it is indicated how the methods developed in this paper may be adapted to solve initial and/or boundary value problems. In particular, we consider the Navier-Stokes equations in three spacial dimensions, subject to an initial condition on the velocity. In this regard, we obtain the existence of a generalized solution to a large class of such initial value problems.      

A comparison study of multishot vs. single-shot DWI-EPI in the neonatal brain: reduced effects of ghosting compared to adults

In the neonatal brain, it is important to use a fast imaging technique to acquire all diffusion weighted images (DWI) for apparent diffusion coefficient (ADC) calculation. Taking into account the occurrence of typical echo planar imaging (EPI) artifacts, we have investigated whether single-shot (SSh) or multishot (MSh) DWI-EPI should be preferred. In 14 neonates, 17 adult patients and 5 adult volunteers, DWIs are obtained both with SSh and MSh EPI. The occurrence of artifacts and their influence on the ADC are explored and further quantified using simulations and phantom studies. Two radiologists scored overall image quality and diagnosability of all images. Single-shot and MSh DWI-EPI scored equally well in neonates with respect to overall image quality and diagnosability. In newborns, more motion artifacts in MSh can be noticed while N/2-ghost artifacts in SSh occur less frequently than in adults. Both N/2-ghost and motion artifacts result in significant ADC abnormalities. There is a serious risk that these artifacts will be mistaken for genuine diffusion abnormalities. N/2-ghost artifacts are hardly noticed in the neonatal brain, which might be due to smaller cerebrospinal fluid (CSF) velocity than in adults. Apparent diffusion coefficient values in MSh are unreliable if motion occurs. We conclude that for ADC calculations in neonates SSh DWI-EPI is more reliable than MSh.