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.     

Effects of precursors on nucleation in atomic layer deposition of HfO2

Atomic layer deposition of hafnium dioxide (HfO₂) on silicon substrates was studied. It was revealed that due to low adsorption probability of HfCl₄ on silicon substrates at higher temperatures (450–600 °C) the growth was non-uniform and markedly hindered in the initial stage of the HfCl₄–H₂O process. In the HfI₄–H₂O and HfI₄–O₂ processes, uniform growth with acceptable rate was obtained from the beginning of deposition. As a result, the HfI₄–H₂O and HfI₄–O₂ processes allowed deposition of smoother, more homogeneous and denser films than the HfCl₄–H₂O process did. The crystal structure developed, however, faster at the beginning of the HfCl₄–H₂O process.     

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.     

Corticomuscular synchronization with small and large dynamic force output

Background  

Over the last few years much research has been devoted to investigating the synchronization between cortical motor and muscular activity as measured by EEG/MEG-EMG coherence. The main focus so far has been on corticomuscular coherence (CMC) during static force condition, for which coherence in beta-range has been described. In contrast, we showed in a recent study [1] that dynamic force condition is accompanied by gamma-range CMC. The modulation of the CMC by various dynamic force amplitudes, however, remained uninvestigated. The present study addresses this question. We examined eight healthy human subjects. EEG and surface EMG were recorded simultaneously. The visuomotor task consisted in isometric compensation for 3 forces (static, small and large dynamic) generated by a manipulandum. The CMC, the cortical EEG spectral power (SP), the EMG SP and the errors in motor performance (as the difference between target and exerted force) were analyzed.     

Rotational spectra of gauche perfluoro-n-butane, C4F10; perfluoro-iso-butane, (CF3)3CF; and tris(trifluoromethyl)methane, (CF3)3CH

The microwave spectra of the gauche conformer of perfluoro-n-butane, n-C₄F₁₀, of perfluoro-iso-butane, (CF₃)₃CF, and of tris(trifluoromethyl)methane, (CF₃)₃CH, have been observed and assigned. The rotational and centrifugal distortion constants for gauche n-C₄F₁₀ are: A = 1058.11750(7) MHz, B = 617.6832(1) MHz, C = 552.18794(1) MHz, Δ_J = 0.0257(5) kHz, δ_J = 0.0052(3) kHz. A C-C-C-C dihedral angle, ω, of ∼55° has been determined. These values agree well with those obtained from a coupled cluster (CCSD/cc-PVTZ) calculation. The rotational and centrifugal distortion constants for iso-C₄F₁₀ and iso-C₄HF₉ are: B_o = 816.4519(4) MHz, D_J = 0.023(2) kHz, and B_o = 903.6985(25) MHz, D_J = 0.043(4) kHz, respectively. The dipole moment of iso-C₄F₁₀ and iso-C₄HF₉ have been measured and found to be 0.0338(8) and 1.69(9) D, respectively.     

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.     

PseudoRiemannian geometry and actions of simple Lie groups

Let G be a connected noncompact simple Lie group acting isometrically on a connected compact pseudoRiemannian manifold M. Denote with $n_0$ and $m_0$ the dimension of the maximal null subspaces tangent to G and M, respectively. Then we always have $n_0?m_0$. Our main result states that, if $n_0=m_0$, then the G-action is, up to a finite covering, an algebraic action. We use this to obtain a complete characterization of a large family of G-actions, thus providing a partial positive answer to the conjecture proposed in Zimmer's program for pseudoRiemannian manifolds. To cite this article: R. Quiroga-Barranco, C. R. Acad. Sci. Paris, Ser. I 341 (2005).