Ensemble methods for classification in cheminformatics

We describe the application of ensemble methods to binary classification problems on two pharmaceutical compound data sets. Several variants of single and ensembles models of k-nearest neighbors classifiers, support vector machines (SVMs), and single ridge regression models are compared. All methods exhibit robust classification even when more features are given than observations. On two data sets dealing with specific properties of drug-like substances (cytochrome P450 inhibition and "Frequent Hitters", i.e., unspecific protein inhibition), we achieve classification rates above 90%. We are able to reduce the cross-validated misclassification rate for the Frequent Hitters problem by a factor of 2 compared to previous results obtained for the same data set with different modeling techniques.     

Synthesis and reactions of 6‐methylsulfanyl‐2,4‐dithioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐carbonitrile

The synthesis of 6‐methylsulfanyl‐2,4‐dithioxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitrile 4 is described. Compound 4 was reacted with various alkylants. The reaction with chloroacetic acid derivatives results in the formation of thieno[2,3‐d]pyrimidines 8 . When methyl iodide was used 2,4,6‐tris(methylsul‐fanyl)pyrimidine‐5‐carbonitrile 5 was obtained. The substitution of the methylsulfanyl groups in compound 5 by several N‐nuclophiles leads to amino substituted pyrimidines.     

Structural and oxidation-state changes at its nonstandard Ni-Fe site during activation of the NAD-reducing hydrogenase from Ralstonia eutropha detected by X-ray absorption, EPR, and FTIR spectroscopy

Structure and oxidation state of the Ni-Fe cofactor of the NAD-reducing soluble hydrogenase (SH) from Ralstonia eutropha were studied employing X-ray absorption spectroscopy (XAS) at the Ni K-edge, EPR, and FTIR spectroscopy. The SH comprises a nonstandard (CN)Ni-Fe(CN)(3)(CO) site; its hydrogen-cleavage reaction is resistant against inhibition by dioxygen and carbon monoxide. Simulations of the XANES and EXAFS regions of XAS spectra revealed that, in the oxidized SH, the Ni(II) is six-coordinated ((CN)O(3)S(2)); only two of the four conserved cysteines, which bind the Ni in standard Ni-Fe hydrogenases, provide thiol ligands to the Ni. Upon the exceptionally rapid reductive activation of the SH by NADH, an oxygen species is detached from the Ni; hydrogen may subsequently bind to the vacant coordination site. Prolonged reducing conditions cause the two thiols that are remote from the Ni in the native SH to become direct Ni ligands, creating a standardlike Ni(II)(CysS)(4) site, which could be further reduced to form the Ni-C (Ni(III)-H(-)) state. The Ni-C state does not seem to be involved in hydrogen cleavage. Two site-directed mutants (HoxH-I64A, HoxH-L118F) revealed structural changes at their Ni sites and were employed to further dissect the role of the extra CN ligand at the Ni. It is proposed that the predominant coordination by (CN),O ligands stabilizes the Ni(II) oxidation state throughout the catalytic cycle and is a prerequisite for the rapid activation of the SH in the presence of oxygen.     

Single-walled carbon nanotube purification, pelletization, and surfactant-assisted dispersion: a combined TEM and resonant micro-raman spectroscopy study

Resonant Raman spectroscopy and transmission electron microscopy were used to characterize the structural changes of three single-walled carbon nanotube samples processed with purification, pelletization, and surfactant-assisted dispersion. A two-stage purification process selectively removes metallic tubes as well as small-diameter ones, enriching large-diameter semiconducting tubes. Pelletizing reduces the intertube distance but greatly increases the intensity ratio of the D band to the G band. Single-walled nanotube (SWNT) bundle size decreases during ultrasonication dispersion aided by a surfactant. SWNT bundles composed of large-diameter tubes are prone to debundling.     

DNS and Experiment of a Turbulent Channel Flow with StreamwiseRotation - Study of the Cross Flow Phenomena

Modelling of rotating turbulent flows is a major issue in engineering applications. Intensive research has been dedicated to rotating channel flows in spanwise direction such as by [1], [2] to name only two. In this work a turbulent channel flow rotating about the streamwise direction is presented. The theory is based on the investigations of [4] employing the symmetry theory. It was found that a cross flow in the spanwise direction is induced. A series of direct numerical simulations (DNS) at different rotation numbers is carried out to examine these effects. Further, the results of the DNS are compared to the measuremets of a corresponding experiment. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Investigating the Selectivity of Triacontyl Interphases

What causes the shape selectivity of C ₃₀ phases? This question can be answered by combining NMR and fluorescence spectroscopies with HPLC separations at various temperatures. The selectivities depend on the ratio of trans to gauche conformations of the alkyl chains, whose dynamic behavior was characterized with a two-dimensional solid-state NMR spectrum (shown on the right).     

Numerical verification of delta shock waves for pressureless gas dynamics

The subject of this paper is theoretical analysis and numerical verification of delta shock wave existence for pressureless gas dynamic system. The existence of overcompressive delta shock wave solution in the framework of Colombeau generalized functions is proved. This result is verified numerically by specially designed procedure that is based on wave propagation method implemented in CLAWPACK. The method is coupled with dynamic refinement mesh. We also consider a strictly hyperbolic system obtained from the original one by perturbation and change of variables. The same numerical procedure is applied to the perturbed problem. The obtained numerical results in both cases confirm theoretical expectations.     

Theoretical studies about the influence of different ring substituents on the nucleophilic ring opening of three-membered heterocycles and possible implications for the mechanisms of cysteine protease inhibitors

Epoxides, aziridines, and thiiranes are electrophilic building blocks that are widely used in synthetic organic chemistry. As a result of their reactivity against nucleophiles they are also used as electrophilic "warheads" for irreversible peptidic or peptidomimetic cysteine protease inhibitors. A general feature of these inhibitors is the remarkable higher inhibition potency of derivatives containing a free carboxylic acid in comparison to corresponding esters. In contrast, experimental investigations about the reaction of methyl thiolate with substituted epoxides revealed a contrary reactivity pattern. These studies also gave information about the regioselectivity of such reactions; however, mechanistic studies were not performed. By analyzing the computed energy profiles of the corresponding reactions we investigate the substituent effects (H vs ester vs carboxylic acid) on the kinetics and thermodynamics of the ring opening by the nucleophile methyl thiolate. Our model computations nicely explain experimental results concerning variations in the reactivities and the regioselectivities and indicate different reasons for the increased inhibition potency of three-membered heterocycles containing an acidic substituent. For aziridines an intramolecular water-mediated acid catalysis seems to be the main reason for the high activity of these inhibitors in acidic media. For epoxides and thiiranes this catalysis is not found, confirming the hypothesis that an ionic interaction between negatively charged carboxylate and the histidinium ion of the active site of the proteases mainly causes the high inhibitory activity of the acids compared to the esters.