Selective flexibility of side-chain residues improves VEGFR-2 docking score using autodock vina

Selective side-chain residue flexibility is an option available on AutoDock Vina docking software. This approach is promising as it attempts to provide a more realistic ligand-protein interaction environment, without an unmanageable increase in computer processing time. However, studies validating this approach are still scarce. VEGFR-2 (vascular endothelial growth factor receptor 2), a known protein target for anti-angiogenic agents, was used in this study. Four residues present in the VEGFR-2 kinase site were selected and made flexible: Lys866, Glu885, Cys917 and Asp1044. The docking scores for all possible combinations of flexible residues were compared to the docking scores using a rigid conformation. The best overall docking scores were obtained using the Glu883 flexible conformation, with pearson and spearman rank correlation values of 0.568 and 0.543, respectively, and a 51% increase in computer processing time. Using different VEGFR-2 X-ray structures a similar trend was observed with Glu885 flexible conformation presenting the best scores. This study demonstrates that careful use of selective side-chain residue flexibility can improve AutoDock Vina docking score accuracy, without a significant increase in computer processing time. This methodology proved to be a valuable tool in drug design when using VEGFR-2 but will also probably be useful if applied to other protein targets.The authors are grateful to Foundation for Science and Technology (Portugal) and COMPETE/QREN/EU for financial support through research project PTDC/QUI-QUI/111060/2009 and Rui M.V. Abreu thanks to SFRH/PROTEC/49450/2009 grant

ChemT, an open-source software for building template-based chemical libraries

In computational chemistry vast quantities of compounds are generated, and there is a need for cheminformatic tools to efficiently build chemical compound libraries. Several software tools for drawing and editing compounds structures are available, but they lack options for automatic generation of chemical libraries. We have implemented ChemT, an easy-to-use open-source software tool that automates the process of preparing custom-made template-based chemical libraries. ChemT automatically generates three-dimensional chemical libraries by inputting a chemical template and the functional groups of interest. The graphical user interface of ChemT is self-explanatory, and a complete tutorial is provided. Several file formats are accepted by ChemT, and it is possible to filter the generated compounds according to different physicochemical properties. The compounds can be subject to force field minimization, and the resulting three-dimensional structures recorded on commonly used file formats. ChemT may be a valuable tool for investigators interested in using in silico virtual screening tools, like QSAR modelling or molecular docking, in order to prioritize compounds for further chemical synthesis. To demonstrate the usefulness of ChemT, we describe an example based on a thieno[3,2-b]pyridine template.Fundação para a Ciência e a Tecnologia (FCT)COMPETE/QREN/E

Synthesis of novel 1-Aryl-3-[2-,3- Or 4-(Thieno[3,2-b]Pyridin-7-Ylthio)Phenyl]Ureas and evaluation as VEGFR2 Tyrosine kinase inhibitors

Vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase is involved in cancer and in angiogenesis. Herein, we report the synthesis of novel1-aryl-3-[2-, 3- or 4-{thieno[3,2-b ]pyridin-7-ylthio) phenyl]ureas as VEGFR2 inhibitors by promoting the regioselective attack of the thiol group of the 4-aminothiophenol in the chlorine nucleophilic displacement on 7-chlorothieno[3,2-b]pyridine 1, obtaining the aminated compounds Za- c. These were reacted with arylisocyanates to give the corresponding 1,3-diarylureas 3a-c, 4a-c and Sa-c (see scheme).Foundation for the Science and Technology (FCT–Portugal) for financial support through the NMR Portuguese network (Bruker 400 Avance III-Univ Minho). FCT and FEDER (European Fund for Regional Development)-COMPETE/QREN/EU for financial support through the research unities PEst-C/QUI/UI686/2011 and PEst-OE/AGR/UI0690/2011, the research project PTDC/QUI- QUI/111060/2009 and the post-Doctoral grant attributed to R.C.C. (SFRH/BPD/68344/2010

Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate derivatives: in vitro evaluation, cell cycle analysis and QSAR studies

Hepatocellular carcinoma (HCC) is a highly complex cancer, resistant to commonly used treatments and new therapeutic agents are urgently needed. A total of thirty-two thieno[3,2-b]pyridine derivatives of two series: methyl 3-amino-6-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates (1a-1t) and methyl 3-amino-6-[(hetero)arylethynyl]thieno[3,2-b]pyridine-2-carboxylates (2a-2n), previously prepared by some of us, were evaluated as new potential anti-HCC agents by studying their in vitro cell growth inhibition on human HepG2 cells and hepatotoxicity using a porcine liver primary cell culture (PLP1). The presence of amino groups linked to a benzene moiety emerges as the key element for the anti-HCC activity. The methyl 3-amino-6-[(3-aminophenyl)ethynyl]thieno[3,2-b]pyridine-2-carboxylate (2f) is the most potent compound presenting GI50 values on HepG2 cells of 1.2 μM compared to 2.9 μM of the positive control ellipticine, with no observed hepatotoxicity (PLP1 GI50>125 μM against 3.3 μM of ellipticine). Moreover this compound changes the cell cycle profile of the HepG2 cells, causing a decrease in the % of cells in the S phase and a cell cycle arrest in the G2/M phase. QSAR studies were also performed and the correlations obtained using molecular and 1D descriptors revealed the importance of the presence of amino groups and hydrogen bond donors for anti-HCC activity, and hydrogen bond acceptors for hepatotoxicity. The best correlations were obtained with 3D descriptors belonging to different subcategories for anti-HCC activity and hepatotoxicity, respectively. These results point to different molecular mechanisms of action of the compounds in anti-HCC activity and hepatotoxicity. This work presents some promising thieno[3,2-b]pyridine derivatives for potential use in the therapy of HCC. These compounds can also be used as scaffolds for further synthesis of more potent analogues.FCT, FEDER/COMPETE/QREN/E

Aminodi(hetero)arylamines in the thieno[3,2-b]pyridine series: synthesis, effects in human tumor cells growth, cell cycle analysis, apoptosis and evaluation of toxicity using non-tumor cells

Three aminodi(hetero)arylamines were prepared via a palladium-catalyzed C-N Buchwald-Hartwig coupling of methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate with different bromonitrobenzenes, followed by reduction of the nitro groups of the coupling products to the corresponding amino compounds. The aminodi(hetero)arylamines thus obtained were evaluated for their growth inhibitory effect on four human tumor cell lines MCF-7 (breast adenocarcinoma), A375-C5 (melanoma), NCI-H460 (non-small cell lung cancer) and HepG2 (hepatocellular carcinoma). The toxicity to non-tumor cells was also evaluated using a porcine liver primary cell culture (PLP1), established by us. The aminodi(hetero)arylamine with the NH2 group in the ortho position and an OMe group in the para position to the NH of the di(hetero)arylamine, is the most promising compound giving the lowest GI50 values (1.30–1.63 μM) in all the tested human tumor cell lines, presenting no toxicity to PLP1 at those concentrations. The effect of this compound on the cell cycle and induction of apoptosis was analyzed in the NCI-H460 cell line. It was observed that it altered the cell cycle profile causing a decrease in the percentage of cells in the G0/G1 phase and an increase of the apoptosis levels.Foundation for the Science and Technology (FCT–Portugal) for financial support through the NMR Portuguese network (Bruker 400 Avance III-Univ Minho). FCT and FEDER (European Fund for Regional Development) for financial support through the research centers PEst-C/QUI/UI686/2011and PEst-OE/AGR/UI0690/2011, the research project PTDC/QUI-QUI/111060/2009 and the post-Doctoralgrants attributed to R.C.C. and R.T.L. (SFRH/BPD/68344/2010 and SFRH/BPD/68787/2010, respectively). IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT

Metabolomic profile and biological properties of sea lavender (Limonium algarvense Erben) plants cultivated with aquaculture wastewaters: implications for its use in herbal formulations and food additives

Water extracts from sea lavender (Limonium algarvense Erben) plants cultivated in greenhouse conditions and irrigated with freshwater and saline aquaculture effluents were evaluated for metabolomics by liquid chromatography-tandem high-resolution mass spectrometry (LC-HRMS/MS), and functional properties by in vitro and ex vivo methods. In vitro antioxidant methods included radical scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric-reducing antioxidant power (FRAP), and copper and iron chelating assets. Flowers’ extracts had the highest compounds’ diversity (flavonoids and its derivatives) and strongest in vitro antioxidant activity. These extracts were further tested for ex vivo antioxidant properties by oxidative haemolysis inhibition (OxHLIA), lipid peroxidation inhibition by thiobarbituric acid reactive substances (TBARS) formation, and anti-melanogenic, anti-tyrosinase, anti-inflammation, and cytotoxicity. Extract from plants irrigated with 300 mM NaCl was the most active towards TBARS (IC50 = 81 µg/mL) and tyrosinase (IC50 = 873 µg/mL). In OxHLIA, the activity was similar for fresh- and saltwater-irrigated plants (300 mM NaCl; IC50 = 136 and 140 µg/mL, respectively). Samples had no anti-inflammatory and anti-melanogenic abilities and were not toxic. Our results suggest that sea lavender cultivated under saline conditions could provide a flavonoid-rich water extract with antioxidant and anti-tyrosinase properties with potential use as a food preservative or as a functional ingredient in herbal supplements.The authors acknowledge the Faculty of Pharmacy and Centre for Neurosciences and Cell Biology (University of Coimbra, Portugal) that kindly offered the murine RAW 264.7 macrophages, and the Functional Biochemistry and Proteomics, and the Marine Molecular Bioengineering groups (Centre of Marine Sciences, Portugal) that provided the human embryonic kidney (HEK) 293, and the human hepatocellular carcinoma (HepG2) cell lines.info:eu-repo/semantics/publishedVersio

Hygienisation, gentrification, and urban displacement in Brazil

This article engages recent debates over gentrification and urban displacement in the global South. While researchers increasingly suggest that gentrification is becoming widespread in “Southern” cities, others argue that such analyses overlook important differences in empirical context and privilege EuroAmerican theoretical frameworks. To respond to this debate, in this article, we outline the concept of higienização (hygienisation), arguing that it captures important contextual factors missed by gentrification. Hygienisation is a Brazilian term that describes a particular form of urban displacement, and is directly informed by legacies of colonialism, racial and class stigma, informality, and state violence. Our objective is to show how “Southern” concepts like hygienisation help urban researchers gain better insight into processes of urban displacement, while also responding to recent calls to decentre and provincialise urban theory

Measurement of charm production at central rapidity in proton-proton collisions at s=2.76\sqrt{s} = 2.76 TeV

The $p_{\rm T}$-differential production cross sections of the prompt (B feed-down subtracted) charmed mesons D$^0$, D$^+$, and D$^{*+}$ in the rapidity range $|y|<0.5$, and for transverse momentum $1< p_{\rm T} <12$ GeV/$c$, were measured in proton-proton collisions at $\sqrt{s} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. The analysis exploited the hadronic decays D$^0 \rightarrow$K$\pi$, D$^+ \rightarrow$K$\pi\pi$, D$^{*+} \rightarrow$D$^0\pi$, and their charge conjugates, and was performed on a $L_{\rm int} = 1.1$ nb$^{-1}$ event sample collected in 2011 with a minimum-bias trigger. The total charm production cross section at $\sqrt{s} = 2.76$ TeV and at 7 TeV was evaluated by extrapolating to the full phase space the $p_{\rm T}$-differential production cross sections at $\sqrt{s} = 2.76$ TeV and our previous measurements at $\sqrt{s} = 7$ TeV. The results were compared to existing measurements and to perturbative-QCD calculations. The fraction of cdbar D mesons produced in a vector state was also determined.Comment: 20 pages, 5 captioned figures, 4 tables, authors from page 15, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/307