Development of docking-based 3D QSAR models for the design of substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors

Abstract

This study has investigated docking-based 3D quantitative structure–activity relationships (QSARs) for a range of quinoline carboxylic acid derivatives by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). A docking study has shown that most of the compounds formed H-bonds with Arg136 and Gln47, which have already been shown to be essential for the binding of ligands at the active site of the hydroorotate dehydrogenase adenovirus (hDHODH). Bioactive conformations of all the molecules obtained from the docking study were used for the 3D QSAR study. The best CoMFA and CoMSIA models were obtained for the training set and were found to be statistically significant, with cross-validated coefficients (q² ) of 0.672 and 0.613, r² _cv of 0.635 and 0.598 and coefficients of determination (r² ) of 0.963 and 0.896, respectively. Both models were validated by a test set of 15 compounds, giving satisfactory predicted correlation coefficients (r² _pred) of 0.824 and 0.793 for the CoMFA and CoMSIA models, respectively. From the docking-based 3D QSAR study we designed 34 novel quinoline-based compounds and performed structure-based virtual screening. Finally, in silico pharmacokinetics and toxicities were predicted for 24 of the best docked molecules. The study provides valuable information for the understanding of interactions between hDHODH and the novel compounds.     

Reflectingness and closed timelike curves in space-time

It is shown by Clarke and Felice (J Phys A Math Gen 15:2415–2417, 1982) that under certain conditions a stationary space-time will produce a closed timelike curve through each point of the space-time. Here a simpler proof and a different version of their theorem are provided.     

Investigation of the Diels-Alder cycloadditions of 2(H)-1,4-oxazin-2-ones

[Reaction: see text]. A variety of 5-chloro-2(H)-1,4-oxazin-2-ones bearing a range of substituents at their 3- and 6-positions undergo Diels-Alder cycloaddition as a 2-azadiene component with electron-rich, electron-deficient, and electron-neutral dienophiles. These reactions proceed with moderate regio- and stereoselectivity to afford relatively stable and readily isolable bridged bicyclic lactone cycloadducts. Chemical manipulation of these cycloadducts affords highly substituted and functionally rich piperidines. The regio- and stereochemical preferences of the cycloadditions of 5-chloro-2(H)-1,4-oxazin-2-ones are investigated computationally using density functional theory (B3LYP/6-31G).     

Interpretation of heart rate variability via detrended fluctuation analysis and alphabeta filter

Detrended fluctuation analysis (DFA), suitable for the analysis of nonstationary time series, has confirmed the existence of persistent long-range correlations in healthy heart rate variability data. In this paper, we present the incorporation of the alphabeta filter to DFA to determine patterns in the power-law behavior that can be found in these correlations. Well-known simulated scenarios and real data involving normal and pathological circumstances were used to evaluate this process. The results presented here suggest the existence of evolving patterns, not always following a uniform power-law behavior, that cannot be described by scaling exponents estimated using a linear procedure over two predefined ranges. Instead, the power law is observed to have a continuous variation with segment length. We also show that the study of these patterns, avoiding initial assumptions about the nature of the data, may confer advantages to DFA by revealing more clearly abnormal physiological conditions detected in congestive heart failure patients related to the existence of dominant characteristic scales.     

Metal-semiconductor transition in single crystal chalcopyrite (CuFeS2)

Electrical and volume measurements to high pressure indicate two phase transitions at 294 K in a natural crystal of chalcopyrite. At 28 kbar there is a semiconductor-semiconductor transition and at 65 kbar a semiconductor-metal transition.     

Causal functions in general relativity

Using the notion of size or volume of future or past of an event, causal functions are defined on a space-time and their behavior is examined in certain space-time models. These functions are then employed to obtain a unified characterization of causality conditions on a spacetime in terms of their simple functional properties like one-oneness, monotonicity, etc. and limiting behavior of these functions along timelike curves. Causal or ideal points boundary of space-time has also been characterized and classified using these causal functions.     

Range and frequency spreadF at Huancayo

The mean occurrence of frequency type of spreadF at Huancayo has been shown to have practically no solar cycle dependence. The occurrence of range type of spreadF is shown to be inversely related to sunspot number. The range spread occurs mostly around 2100 LT for any of the solar epoch, while frequency spread has maximum occurrence between 2300 and 0000 LT in high sunspot years and between 0000 and 0100 LT in low sunspot years. The seasonal variation in the occurrence of either type of spreadF shows minimum in northern solstices (June months) and maximum occurrence in southern solstices (December months). The post-sunset rise ofF layer is most predominant during high sunspot years. These results point out the inadequacy of the theory of spreadF based entirely on the post-sunset upward rise of theF region after sunset.     

Band structure of palladium hydride by the augmented-plane-wave method

The band structure of palladium hydride (PdH) is calculated using the augmented-plane-wave method. Using these calculations the Fermi energy, Fermi surface, de Haas-van Alphen frequencies, and density of states have been determined. These results are compared with our previous calculations for Pd and with other reported results for PdH.