Empirical formulae for the influence of real film thickness distribution on the capacitance of an EHL point contact and application to rolling bearings

Electrical bearing capacitance plays an important role in the prediction of harmful bearing currents, which could lead to premature failure of the bearing and the entire drive system. The effect of rolling speed, force, and material parameters on the electrical capacitance of an elliptical contact in elastohydrodynamic lubrication has been studied numerically. An empirical equation that describes the relationship between the areas of central film thickness and minimum film thickness of the HERTZ'ian contact area has been derived. Additional, another formula to calculate the total capacitance of a rolling bearing, based only on the HERTZ'ian contact capacitance with the central film thickness as single parameter, has been developed. Finally, a comparison was made between the calculated capacities and measured values

Comprehensive knowledge base of two- and three-dimensional activity cliffs for medicinal and computational chemistry [v1; ref status: indexed, http://f1000r.es/5ir]

Activity cliffs are formed by pairs or groups of structurally similar or analogous active compounds with large differences in potency. They can be defined in two or three dimensions by comparing graph-based molecular representations or compound binding modes, respectively. Through systematic analysis of publicly available compound activity data and ligand-target X-ray structures we have in a series of studies determined all currently available two- and three-dimensional activity cliffs (2D- and 3D-cliffs, respectively). Furthermore, we have systematically searched for 2D extensions of 3D-cliffs. Herein, we specify different categories of activity cliffs we have explored and introduce an open access data deposition in ZENODO (doi: 10.5281/zenodo.18490) that makes the entire knowledge base of current activity cliffs freely available in an organized form

Classification of Binding Modes for Kinase-Inhibitor Complex Structures, 3D Activity Cliffs Formed by Kinase Inhibitors, and Structural Analogues of 3D-Cliff Compounds

<p>The classification of crystallographic binding modes is provided for 884 kinase-inhibitor complex structures that were assembled from PDB. In addition, a total of 105 three-dimensional activity cliffs formed by 3D kinase inhibitors are listed. Their corresponding potency information is also given. Furthermore, the 2D structural analogues of 3D cliff-forming inhibitors were identified from ChEMBL database, on the basis of matched molecular pairs. These analogs and their activity information are also provided.</p

Current Compound Coverage of the Kinome

Publicly available kinase inhibitors have been analyzed in detail. Nearly 19000 inhibitors have been identified with activity against 266 different kinases. Thus, about half of the human kinome is currently covered with active small molecules. The distribution of inhibitors across the kinome is uneven. Most available kinase inhibitors are likely to be type I inhibitors. By contrast, type II inhibitors are rare but usually have high potency. Kinase inhibitors generally display high scaffold diversity. Activity cliffs with an at least 100-fold difference in potency are only found for inhibitors of 106 kinases, which is partly due to only small numbers of compounds available for many kinases, in addition to scaffold diversity. Moreover, kinase inhibitors are less promiscuous than often thought. More than 70% of available inhibitors are only annotated with a single kinase activity, and only ∼1% of the inhibitors are active against five or more kinases

Knowledge base of two- and three-dimensional activity cliffs

<p>The result of up-to-date surveys and systematic analyses of 2D-cliffs including clusters, 3D-cliffs, and extensions of 3D-cliffs is made freely available in four separate data files. These files contain the list of 2D-cliffs and cliff clusters, 3D-cliffs, 3D-cliff-MMPs, and superpositions of complex X-ray structures and 3D ligands for selected targets. The data organization and information is detailed in <em>README.doc</em>.</p> <p> </p

Systematic Identification and Classification of Three-Dimensional Activity Cliffs

Activity cliffs were systematically extracted from public domain X-ray structures of targets for which complexes with multiple ligands were available, following the concept of three-dimensional (3D) cliffs. Binding modes of ligands with well-defined potency measurements were compared in a pairwise manner, and their 3D similarity was calculated using a previously reported property density function-based method taking conformational, positional, and chemical differences into account. Requiring the presence of at least 80% 3D similarity and a potency difference of at least 2 orders of magnitude as cliff criteria, a total of 216 well-defined 3D activity cliffs were detected in the Protein Data Bank (PDB). These 3D-cliffs involved a total of 269 ligands active against 38 different targets belonging to 17 protein families. For 255 of these compounds, binding modes were available at high crystallographic resolution. All 3D-cliffs were analyzed in detail and assigned to different categories on the basis of crystallographic interaction patterns. In many instances, differences in ligand–target interactions suggested plausible causes for origins of 3D-cliffs. In other cases, short-range interactions seen in X-ray structures were insufficient to deduce possible reasons for cliff formation. The 3D-cliffs described herein further advance the rationalization of activity cliffs at the level of ligand–target interactions and should also be useful for other applications such as the calibration of energy functions for structure-based design. The pool of identified activity cliffs is provided to enable subsequent structure-based analyses of cliffs

Currently available 3D activity cliffs and 2D-analogs of 3D-cliff compounds

<p>Three dimensional activity cliffs (3D-cliffs) were systematically determined based on currently available X-ray structures in PDB. The list of all 236, 292, 595 3D-cliffs that were identified from the K_i, IC₅₀, and K_i/IC₅₀ sets, respectively, is provided. In addition, on the basis of matched molecular pairs, the 2D structural analogs of 3D-cliff compounds identified from ChEMBL database (release 19) are given.</p

Chalcone Isomerase from Eubacterium ramulus Catalyzes the Ring Contraction of Flavanonols

The enzyme catalyzing the ring-contracting conversion of the flavanonol taxifolin to the auronol alphitonin in the course of flavonoid degradation by the human intestinal anaerobe Eubacterium ramulus was purified and characterized. It stereospecifically catalyzed the isomerization of (+)-taxifolin but not that of (-)-taxifolin. The Km for (+)-taxifolin was 6.4 ± 0.8 μM, and the Vmax was 108 ± 4 μmol min-1 (mg protein)-1 The enzyme also isomerized (+)-dihydrokaempferol, another flavanonol, to maesopsin. Inspection of the encoding gene revealed its complete identity to that of the gene encoding chalcone isomerase (CHI) from E. ramulus Based on the reported X-ray crystal structure of CHI (M. Gall et al., Angew Chem Int Ed 53:1439-1442, 2014, http://dx.doi.org/10.1002/anie.201306952), docking experiments suggest the substrate binding mode of flavanonols and their stereospecific conversion. Mutation of the active-site histidine (His33) to alanine led to a complete loss of flavanonol isomerization by CHI, which indicates that His33 is also essential for this activity. His33 is proposed to mediate the stereospecific abstraction of a proton from the hydroxymethylene carbon of the flavanonol C-ring followed by ring opening and recyclization. A flavanonol-isomerizing enzyme was also identified in the flavonoid-converting bacterium Flavonifractor plautii based on its 50% sequence identity to the CHI from E. ramulus IMPORTANCE: Chalcone isomerase was known to be involved in flavone/flavanone conversion by the human intestinal bacterium E. ramulus Here we demonstrate that this enzyme moreover catalyzes a key step in the breakdown of flavonols/flavanonols. Thus, a single isomerase plays a dual role in the bacterial conversion of dietary bioactive flavonoids. The identification of a corresponding enzyme in the human intestinal bacterium F. plautii suggests a more widespread occurrence of this isomerase in flavonoid-degrading bacteria