Updates in Rhea-a manually curated resource of biochemical reactions.

Rhea (http://www.ebi.ac.uk/rhea) is a comprehensive and non-redundant resource of expert-curated biochemical reactions described using species from the ChEBI (Chemical Entities of Biological Interest) ontology of small molecules. Rhea has been designed for the functional annotation of enzymes and the description of genome-scale metabolic networks, providing stoichiometrically balanced enzyme-catalyzed reactions (covering the IUBMB Enzyme Nomenclature list and additional reactions), transport reactions and spontaneously occurring reactions. Rhea reactions are extensively curated with links to source literature and are mapped to other publicly available enzyme and pathway databases such as Reactome, BioCyc, KEGG and UniPathway, through manual curation and computational methods. Here we describe developments in Rhea since our last report in the 2012 database issue of Nucleic Acids Research. These include significant growth in the number of Rhea reactions and the inclusion of reactions involving complex macromolecules such as proteins, nucleic acids and other polymers that lie outside the scope of ChEBI. Together these developments will significantly increase the utility of Rhea as a tool for the description, analysis and reconciliation of genome-scale metabolic models

Qualitative prediction of blood–brain barrier permeability on a large and refined dataset

The prediction of blood–brain barrier permeation is vitally important for the optimization of drugs targeting the central nervous system as well as for avoiding side effects of peripheral drugs. Following a previously proposed model on blood–brain barrier penetration, we calculated the cross-sectional area perpendicular to the amphiphilic axis. We obtained a high correlation between calculated and experimental cross-sectional area (r = 0.898, n = 32). Based on these results, we examined a correlation of the calculated cross-sectional area with blood–brain barrier penetration given by logBB values. We combined various literature data sets to form a large-scale logBB dataset with 362 experimental logBB values. Quantitative models were calculated using bootstrap validated multiple linear regression. Qualitative models were built by a bootstrapped random forest algorithm. Both methods found similar descriptors such as polar surface area, pKa, logP, charges and number of positive ionisable groups to be predictive for logBB. In contrast to our initial assumption, we were not able to obtain models with the cross-sectional area chosen as relevant parameter for both approaches. Comparing those two different techniques, qualitative random forest models are better suited for blood-brain barrier permeability prediction, especially when reducing the number of descriptors and using a large dataset. A random forest prediction system (ntrees = 5) based on only four descriptors yields a validated accuracy of 88%

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

Density-Functional Theory Investigation of the Geometric, Energetic, and Optical Properties of the Cobalt(II)tris(2,2'-bipyridine) Complex in the High-Spin and the Jahn-Teller Active Low-Spin States

State-of-the-art generalized gradient approximation (GGA) (PBE, OPBE, RPBE, OLYP, and HCTH), meta-GGA (VSXC and TPSS), and hybrid (B3LYP, B3LYP*, O3LYP, and PBE0) functionals are compared for the determination of the structure and the energetics of the D3 [Co(bpy)3]2+ complex in the 4A2 and 4E trigonal components of the high-spin 4T1g(t2g5 e g2) state and in the low-spin 2E state of octahedral 2Eg(t2g6 e g1) parentage. Their comparison extends also to the investigation of the Jahn-Teller instability of the 2E state through the characterization of the extrema of C2 symmetry of this spin state's potential energy surface. The results obtained for [Co(bpy) 3]2+ in either spin manifold are very consistent among the functionals used and are in good agreement with available experimental data. The functionals, however, perform very differently with respect to the spin-state energetics because the calculated values of the high-spin/low-spin energy difference ΔEHLel vary between -3212 and 3919 cm-1. Semilocal functionals tend to give too large ΔE HLel values and thus fail to correctly predict the high-spin state as the ground state of the isolated complex, while hybrid functionals tend to overestimate the stability of the high-spin state with respect to the low-spin state. Reliable results are, however, obtained with the OLYP, HCTH, B3LYP*, and O3LYP functionals which perform best for the description of the isolated complex. The optical properties of [Co(bpy) 3]2+ in the two spin states are also analyzed on the basis of electronic excitation calculations performed within time-dependent density functional response theory. The calculated absorption and circular dichroism spectra agree well with experimental results

Spin-crossover in cobalt(II) imine complexes

Whereas there are hundreds of known iron(II) spin-crossover compounds, only a handful of cobalt(II) spin-crossover compounds have been discovered to date, and hardly an in depth study on any of them exists. This review begins with an introduction into the theoretical aspects to be considered when discussing spin-crossover compounds in general and cobalt(II) systems in particular. It is followed by case studies on [Co(bpy)3]2+ and [Co(terpy)2]2+ (bpy = 2,2′-bipyridine, terpy = 2,2′:6′,2″-terpyridine) presenting and discussing results from magnetic susceptibility measurements, X-ray crystallography, optical spectroscopy, and EPR spectroscopy

Preclinical evaluation of drug combinations identifies co-inhibition of Bcl-2/XL/W and MDM2 as a potential therapy in uveal melanoma

Introduction: Uveal melanoma (UM) is a rare and malignant intraocular tumour with a dismal prognosis. Despite a good control of the primary tumour by radiation or surgery, up to 50% of patients subsequently develop metastasis for which no efficient treatment is yet available.Methodology: To identify therapeutic opportunities, we performed an in vitro screen of 30 combinations of different inhibitors of pathways that are dysregulated in UM. Effects of drug combinations on viability, cell cycle and apoptosis were assessed in eight UM cell lines. The best synergistic combinations were further evaluated in six UM patient-derived xenografts (PDXs).Results: We demonstrated that the Bcl-2/X-L/W inhibitor (ABT263) sensitised the UM cell lines to other inhibitors, mainly to mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase (MEK) and murine double minute 2 (MDM2) inhibitors. mTOR (RAD001) and MEK1/2 (trametinib) inhibitors were efficient as single agents, but their combinations with ABT263 displayed no synergism in UM PDXs. In contrast, the combination of ABT263 with MDM2 inhibitor (HDM201) showed a trend for a synergistic effect.Conclusion: We showed that inhibition of Bcl-2/X-L/W sensitised the UM cell lines to other treatments encouraging investigation of the underlying mechanisms. Furthermore, our findings highlighted Bcl-2/X-L/W and MDM2 co-inhibition as a promising strategy in UM. (C) 2019 The Author(s). Published by Elsevier Ltd

STEM and STXM-XANES analysis of FIB sections of Ultracarbonaceous Antarctic Micrometeorites (UCAMMs)

International audienceIntroduction: Ultracarbonaceous Antarctic Micrometeorites (UCAMMS) are extraterrestrial dust particles containing large amount of carbonaceous material with elevated D/H ratios [1] and high N/C atomic ratio (up to 0.2)[2]. UCAMMS are rare (~ 1% of the particles in the Concordia meteorite collection) but they have been identified in several collection of interplanetary dust [3, 4]. They are most probably of cometary origin. Here, we studied the association of organic matter and minerals by scanning transmission X-ray microscopy (STXM-XANES) coupled with scanning transmission electronic microscopy (TEM/STEM). Samples and Methods: The UCAMMs studied here were collected in the Antarctic snow, close to the Concordia station at Dome C [3]. FIB sections of 8 UCAMMs (DC06-18, DC06-41, DC06-43, DC06-65, DC06-308, DC06-139, DC16-30, DC16-309) were analyzed using synchrotron based STXM-XANES at the carbon, nitrogen and oxygen K-edges. The FIB sections were subsequently analyzed with transmission electron microscopy (TEM/STEM) using a FEI Tecnai G2 20 and a FEI TITAN Themis 300 [5, 6]. Peak identification of STXM-XANES spectra are based on [7]. XANES spectra are processed and quantified using Quantorxs method [8] and quantification of STEM EDS spectra has been realized using Hyperspy software [9]. Here, we mainly present results obtained on two recently identified UCAMMs (DC06-308 and DC16-309) and compare them with previous observations [1, 5, 6]. Results: The STXM-XANES analysis reveals 3 types of organic matter (OM) characterized by different carbon speciation. Figure 1 shows type I OM in blue and type II OM in green, both having spectra close to that of chondritic insoluble organic matter (IOM). The main peaks of type I and II OMs are found around 284.8 eV (aromatic and olefinic groups (C=C)), 286.4 eV (ketone and phenol C=O) and 288.4 eV (carboxyl O=C-O). Type II OM exhibits similar functional groups as type I OM but the first peak position is shifted to 285 eV, indicating a stronger contribution of the aromatic groups. The atomic N/C ratio of types I/II OMs range between 0.01 and 0.05 (1σ=0.02) similar to those of chondritic IOM. The type III, in red on Figure 1 exhibits larger differences. The main peak is at 286.4 eV (C≡N nitrile), a small peak at 284.8 eV (alken